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Cancer Pain (PDQ®)–Health Professional Version


Cancer Pain (PDQ®)–Health Professional Version

General Information About Cancer Pain

Go to Patient Version

Pain is one of the most common symptoms in cancer patients and often has a negative impact on patients’ functional status and quality of life (QOL). The goal of the following summary is to provide evidence-based, up-to-date, and practical information on the management of cancer pain.

Effective pain management can generally be accomplished by paying attention to the following steps:[1]

  1. Regular screening to ensure that the patient’s pain is recognized early. For more information, see the Pain Assessment section.
  2. Proper characterization of the pain to identify underlying pathophysiology, which could significantly influence treatment options. For more information, see the Pain Classification section.
    • Is the pain acute or chronic?
    • Is it secondary to cancer, cancer treatment, other causes, or a combination?
    • Is it somatic, visceral, neuropathic, or mixed?
    • Is there an incidental component?
    • Is there breakthrough pain?
  3. Determining whether the pain requires pharmacological and/or other modalities of treatment. Pain is often multifactorial in nature, so factors that may modulate pain expression, such as psychological distress and substance use, should be assessed. For more information, see the Background and Definitions section.
    • What is the impact of pain on the patient?
    • Is the benefit of treatment likely going to outweigh the risks?
  4. Identifying the optimal pharmacological and nonpharmacological treatment options, including referrals to specialists, if needed. For more information, see the sections on Pharmacological Therapies for Pain Control and Modalities for Pain Control: Other Approaches. Complex pain often requires multidimensional interdisciplinary evaluation and intervention. There are many issues to consider when determining the most appropriate treatment, such as the following:
    • Previous pain treatments.
    • Patient prognosis.
    • Predictive factors for pain control (e.g., psychological distress).
    • Impact on function.
    • Comorbidities (e.g., renal or hepatic failure).
    • Risk of misuse of or addiction to pain medications.
    • Patient preference.
  5. Providing proper education about treatment, including medication administration, expected side effects and associated treatments, and when patients can expect improvement. If opioids are considered, fear of opioids and the risks of opioid use and misuse should be addressed. Patients and family caregivers should be educated about the safe storage, use, and disposal of opioids. One study demonstrated that improper use, storage, and disposal are common among cancer outpatients.[2]
  6. Monitoring the patient longitudinally with return visits to titrate/adjust treatments. Patients with cancer or noncancer pain requiring chronic therapy are monitored closely to optimize treatment and to minimize the likelihood of complications of opioid use, including misuse or abuse. The risks and benefits of opioid use are evaluated regularly, and physician impressions are discussed openly with the patient.

Background and Definitions

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”[3] Pain is commonly experienced by cancer patients. Its proper assessment requires the following:

  • Measuring pain location(s), intensity, quality, and other factors.
  • Clarifying the impact of pain on patients’ psychological, social, spiritual, and existential domains.
  • Establishing treatment adherence and responsiveness.

Pain intensity may be assessed by asking patients to rate their pain on a numeric rating scale (NRS) of 0 to 10, with 0 defined as no pain and 10 defined as the worst pain imaginable. Although highly subjective, this scale may assist practitioners in gauging a patient’s pain status.[4] A commonly used approach to pain management employs the three-step World Health Organization pain relief ladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength.[5]

Familiarity with opioid pharmacokinetics, equianalgesic dosing, and adverse effects is necessary for their safe and effective use. The appropriate use of adjuvant pharmacological and nonpharmacological interventions is needed to optimize pain management.

Prevalence

Pain occurs in 20% to 50% of patients with cancer.[6] Roughly 80% of patients with advanced-stage cancer have moderate to severe pain.[7] One meta-analysis looking at pooled data from 52 studies found that more than half of patients had pain.[8] Younger patients are more likely to experience cancer pain and pain flares than are older patients.[9]

Causes of Cancer Pain: Cancer, Cancer Treatments, and Comorbidities

A study evaluating the characteristics of patients (N = 100) with advanced cancer presenting to a palliative care service found the primary tumor as the chief cause of pain in 68% of patients.[10] Most pain was somatic, and pain was as likely to be continuous as intermittent.

Pain can be caused by the following:

  • Surgery.
  • Radiation therapy.
  • Chemotherapy.
  • Targeted therapy.
  • Supportive care therapies.
  • Diagnostic procedures.

A systematic review of the literature identified reports of pain occurring in 59% of patients receiving anticancer treatment and in 33% of patients after curative treatments.[8] The prevalence of chronic nonmalignant pain—such as chronic low back pain, osteoarthritis pain, fibromyalgia, and chronic daily headaches—has not been well characterized in cancer patients. It has been reported to range from 2% to 76%, depending on the patient population and how pain was assessed.[11–14]

Postoperative pain

Pain is an expected consequence of surgery. Concerns about the prevalence of opioid misuse have drawn increasing attention to how opioids are prescribed in common settings, including postoperatively. Studies suggest widespread variation in the prescribing patterns of opioids in the postoperative setting.[15] One study of opioid use after orthopedic and general surgery procedures found that, on average, only between 19% and 34% of the opioids prescribed were used and that the quantity of opioids prescribed after a given procedure varied widely by provider.[15] This finding led to the evaluation of utilization data and recommendations for standardizing the quantity of opioids prescribed for five common general surgery procedures.[16] An educational intervention based on those recommendations was associated with a 53% decrease in prescribed opioids after those five general surgery procedures, with only 1 patient in a cohort of 246 patients requiring an opioid refill.[17]

The opioid epidemic has also raised questions about whether postoperative use of opioids can lead to misuse. New persistent opioid use develops in 6% to 8% of opioid-naïve patients after noncancer surgery.[18–20] In a large retrospective analysis of patients undergoing curative-intent cancer surgery, 10.4% of opioid-naïve patients developed new persistent opioid use, defined as filling opioid prescriptions 90 to 180 days after surgery. At 1 year postsurgery, these patients were using an average of six 5-mg hydrocodone (or equivalent) tablets per day. Among the risk factors evaluated, only the use of adjuvant chemotherapy increased the risk of new persistent opioid use (15%–21% risk with adjuvant chemotherapy vs. 7%–11% risk with no chemotherapy).[21] In summary, one in ten patients undergoing curative-intent cancer surgery may be at risk of postoperative persistent opioid use.

Infusion-related pain syndromes

The infusion of intravenous chemotherapy causes four pain syndromes:[22–24]

  • Venous spasm, which is treated by the application of a warm compress or a decrease in the infusion rate.
  • Chemical phlebitis, which may result from chemotherapy or nonchemotherapy infusions such as potassium chloride and hyperosmolar solutions.[23]
  • Vesicant extravasation, which may cause intense pain followed by desquamation and ulceration.[22]
  • Anthracycline-associated flare, a venous flare reaction that may be caused by doxorubicin and includes local urticaria, pain, or stinging.[24]

Some chemotherapy agents such as vinorelbine may cause pain at the tumor site.[25]

Treatment-related mucositis

Severe mucositis often occurs as a consequence of myeloablative chemotherapy and standard-intensity therapy.[26] Cytotoxic agents commonly associated with mucositis are cytarabine, doxorubicin, etoposide, fluorouracil (5-FU), and methotrexate. Epidermal growth factor receptor (EGFR) inhibitors, multitargeted tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors also cause mucositis.[27,28] Risk factors for mucositis include preexisting oral pathology, poor dental hygiene, and younger age.[26]

White blood cell growth factor–related bone pain

Filgrastim and pegfilgrastim are recombinant granulocyte colony-stimulating factors (G-CSFs) that increase proliferation and differentiation of neutrophil precursors. Ostealgia is a significant adverse effect caused by G-CSFs that can occur in 20% to 71% of patients.[29] This bone pain starts within 2 days of a pegfilgrastim dose and lasts for 2 to 4 days. Although the mechanism by which G-CSFs cause bone pain is largely unknown, it is hypothesized that histamine release, creating local inflammation and edema, may play a role. A phase II trial randomly assigned patients who had experienced bone pain with pegfilgrastim to receive either daily loratadine 10 mg for 7 days or matching placebo after subsequent doses of pegfilgrastim.[30] There was no statistically significant difference between the two arms.

A second phase II trial randomly assigned patients receiving pegfilgrastim to receive naproxen, loratadine, or no preventative medications.[31] The percentage of patients experiencing any grade bone pain was 40.3% in the naproxen group, 42.5% in the loratadine group, and 46.6% in the no-prophylaxis group. Although there was no statistically significant difference between treatment groups, the authors concluded that loratadine administration has a favorable risk-to-benefit profile and should be considered.

Conventional pain medications have also been studied in this area. A phase III, double-blind, placebo-controlled trial of naproxen for the prevention of pegfilgrastim-induced bone pain randomly assigned patients to receive either naproxen 500 mg twice daily for 5 to 8 days after pegfilgrastim administration or placebo.[32] Naproxen reduced overall pain intensity and duration of pain, compared with placebo.

Chemotherapy-related musculoskeletal pain

Paclitaxel generates a syndrome of diffuse arthralgias and myalgias in 10% to 20% of patients.[33] Diffuse pain in joints and muscles appears 1 to 2 days after the infusion and lasts a median of 4 to 5 days. Pain originates in the back, hips, shoulders, thighs, legs, and feet. Weight bearing, walking, or tactile contact exacerbates the pain. Steroids may reduce the tendency to develop myalgia and arthralgias. Among hormonal therapies, aromatase inhibitors cause musculoskeletal symptoms, osteoporotic fractures, arthralgias, and myalgias.[34]

Dermatologic complications and chemotherapy

EGFR inhibitors cause dermatitis with ensuing pain.[35] Acute herpetic neuralgia occurs with a significantly increased incidence among cancer patients, especially those with hematologic malignancies and those receiving immunosuppressive therapies.[36] The pain usually resolves within 2 months but can persist and become postherpetic neuralgia. The palmar-plantar erythrodysesthesia syndrome is observed in association with continuously infused 5-FU, capecitabine,[37] liposomal doxorubicin,[38] and paclitaxel.[39] Targeted agents such as sorafenib and sunitinib are also associated with hand-foot–like syndrome.[40] Patients develop tingling or burning in their palms and soles, followed by an erythematous rash. Management often requires discontinuing therapy or reducing the treatment dose.

Supportive care therapies and pain

Supportive care therapies can cause pain, as typified by bisphosphonate-associated osteonecrosis of the jaw.[41] Corticosteroid use has also been associated with the development of avascular necrosis.[42]

Radiation-induced pain

Radiation is associated with several distinct pain syndromes. First, patients may experience pain from brachytherapy and from positioning during treatment (i.e., placement on a radiation treatment table). Second, delayed tissue damage such as mucositis, mucosal inflammation in areas receiving radiation, and dermatitis may be painful. Third, a temporary worsening of pain in the treated area (a pain flare) is a potential side effect of radiation treatment for bone metastases.[43] A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo.[44] For more information, see the External-Beam Radiation Therapy section.

Impact on Function and QOL

Cancer pain is associated with increased emotional distress. Both pain duration and pain severity correlate with risk of developing depression. Cancer patients are disabled an average of 12 to 20 days per month, with 28% to 55% unable to work because of their cancer.[45] Cancer survivors may experience distress when their pain unexpectedly persists after completion of cancer treatments.[46] Survivors also experience loss of support from their previous health care team as oncologists transition their care back to primary care providers.

In one study, between 20% and 50% of cancer patients continued to experience pain and functional limitations years posttreatment.[47] Untreated pain leads to requests for physician-assisted suicide.[48] Untreated pain also leads to unnecessary hospital admissions and visits to emergency departments.[49]

References
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  4. Oldenmenger WH, de Raaf PJ, de Klerk C, et al.: Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. J Pain Symptom Manage 45 (6): 1083-93, 2013. [PUBMED Abstract]
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  9. Green CR, Hart-Johnson T: Cancer pain: an age-based analysis. Pain Med 11 (10): 1525-36, 2010. [PUBMED Abstract]
  10. Gutgsell T, Walsh D, Zhukovsky DS, et al.: A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care 20 (2): 140-8, 2003 Mar-Apr. [PUBMED Abstract]
  11. Caraceni A, Portenoy RK: An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain 82 (3): 263-74, 1999. [PUBMED Abstract]
  12. Barbera L, Molloy S, Earle CC: Frequency of non-cancer-related pain in patients with cancer. J Clin Oncol 31 (22): 2837, 2013. [PUBMED Abstract]
  13. Childers JW, King LA, Arnold RM: Chronic Pain and Risk Factors for Opioid Misuse in a Palliative Care Clinic. Am J Hosp Palliat Care 32 (6): 654-9, 2015. [PUBMED Abstract]
  14. Massaccesi M, Deodato F, Caravatta L, et al.: Incidence and management of noncancer pain in cancer patients referred to a radiotherapy center. Clin J Pain 29 (11): 944-7, 2013. [PUBMED Abstract]
  15. Kim N, Matzon JL, Abboudi J, et al.: A Prospective Evaluation of Opioid Utilization After Upper-Extremity Surgical Procedures: Identifying Consumption Patterns and Determining Prescribing Guidelines. J Bone Joint Surg Am 98 (20): e89, 2016. [PUBMED Abstract]
  16. Hill MV, McMahon ML, Stucke RS, et al.: Wide Variation and Excessive Dosage of Opioid Prescriptions for Common General Surgical Procedures. Ann Surg 265 (4): 709-714, 2017. [PUBMED Abstract]
  17. Hill MV, Stucke RS, McMahon ML, et al.: An Educational Intervention Decreases Opioid Prescribing After General Surgical Operations. Ann Surg 267 (3): 468-472, 2018. [PUBMED Abstract]
  18. Clarke H, Soneji N, Ko DT, et al.: Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ 348: g1251, 2014. [PUBMED Abstract]
  19. Soneji N, Clarke HA, Ko DT, et al.: Risks of Developing Persistent Opioid Use After Major Surgery. JAMA Surg 151 (11): 1083-1084, 2016. [PUBMED Abstract]
  20. Brummett CM, Waljee JF, Goesling J, et al.: New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg 152 (6): e170504, 2017. [PUBMED Abstract]
  21. Lee JS, Hu HM, Edelman AL, et al.: New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery. J Clin Oncol 35 (36): 4042-4049, 2017. [PUBMED Abstract]
  22. Sauerland C, Engelking C, Wickham R, et al.: Vesicant extravasation part I: Mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum 33 (6): 1134-41, 2006. [PUBMED Abstract]
  23. Pucino F, Danielson BD, Carlson JD, et al.: Patient tolerance to intravenous potassium chloride with and without lidocaine. Drug Intell Clin Pharm 22 (9): 676-9, 1988. [PUBMED Abstract]
  24. Curran CF, Luce JK, Page JA: Doxorubicin-associated flare reactions. Oncol Nurs Forum 17 (3): 387-9, 1990 May-Jun. [PUBMED Abstract]
  25. Long TD, Twillman RK, Cathers-Schiffman TA, et al.: Treatment of vinorelbine-associated tumor pain. Am J Clin Oncol 24 (4): 414-5, 2001. [PUBMED Abstract]
  26. Peterson DE, Lalla RV: Oral mucositis: the new paradigms. Curr Opin Oncol 22 (4): 318-22, 2010. [PUBMED Abstract]
  27. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al.: Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19 (8): 1079-95, 2011. [PUBMED Abstract]
  28. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al.: Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 17 (1): 135-44, 2012. [PUBMED Abstract]
  29. Moore DC, Pellegrino AE: Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management. Ann Pharmacother 51 (9): 797-803, 2017. [PUBMED Abstract]
  30. Moukharskaya J, Abrams DM, Ashikaga T, et al.: Randomized phase II study of loratadine for the prevention of bone pain caused by pegfilgrastim. Support Care Cancer 24 (7): 3085-93, 2016. [PUBMED Abstract]
  31. Kirshner JJ, McDonald MC, Kruter F, et al.: NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim. Support Care Cancer 26 (4): 1323-1334, 2018. [PUBMED Abstract]
  32. Kirshner JJ, Heckler CE, Janelsins MC, et al.: Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base. J Clin Oncol 30 (16): 1974-9, 2012. [PUBMED Abstract]
  33. Loprinzi CL, Maddocks-Christianson K, Wolf SL, et al.: The Paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism. Cancer J 13 (6): 399-403, 2007 Nov-Dec. [PUBMED Abstract]
  34. Coleman RE, Bolten WW, Lansdown M, et al.: Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations. Cancer Treat Rev 34 (3): 275-82, 2008. [PUBMED Abstract]
  35. Lynch TJ, Kim ES, Eaby B, et al.: Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12 (5): 610-21, 2007. [PUBMED Abstract]
  36. Portenoy RK, Duma C, Foley KM: Acute herpetic and postherpetic neuralgia: clinical review and current management. Ann Neurol 20 (6): 651-64, 1986. [PUBMED Abstract]
  37. Gressett SM, Stanford BL, Hardwicke F: Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 12 (3): 131-41, 2006. [PUBMED Abstract]
  38. Alberts DS, Garcia DJ: Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 54 (Suppl 4): 30-5, 1997. [PUBMED Abstract]
  39. Vukelja SJ, Baker WJ, Burris HA, et al.: Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. J Natl Cancer Inst 85 (17): 1432-3, 1993. [PUBMED Abstract]
  40. Chu D, Lacouture ME, Fillos T, et al.: Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 47 (2): 176-86, 2008. [PUBMED Abstract]
  41. Prommer EE: Toxicity of bisphosphonates. J Palliat Med 12 (11): 1061-5, 2009. [PUBMED Abstract]
  42. Mattano LA, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012. [PUBMED Abstract]
  43. Ripamonti CI, Bossi P, Santini D, et al.: Pain related to cancer treatments and diagnostic procedures: a no man’s land? Ann Oncol 25 (6): 1097-106, 2014. [PUBMED Abstract]
  44. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015. [PUBMED Abstract]
  45. Brown LF, Kroenke K, Theobald DE, et al.: The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology 19 (7): 734-41, 2010. [PUBMED Abstract]
  46. Jim HS, Andersen BL: Meaning in life mediates the relationship between social and physical functioning and distress in cancer survivors. Br J Health Psychol 12 (Pt 3): 363-81, 2007. [PUBMED Abstract]
  47. Harrington CB, Hansen JA, Moskowitz M, et al.: It’s not over when it’s over: long-term symptoms in cancer survivors–a systematic review. Int J Psychiatry Med 40 (2): 163-81, 2010. [PUBMED Abstract]
  48. Foley KM: The relationship of pain and symptom management to patient requests for physician-assisted suicide. J Pain Symptom Manage 6 (5): 289-97, 1991. [PUBMED Abstract]
  49. Mayer DK, Travers D, Wyss A, et al.: Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 29 (19): 2683-8, 2011. [PUBMED Abstract]

Pain Classification

Total Pain

The concept of total pain captures its multidimensional nature by explicitly including the physical, psychological, social, and spiritual components of pain.[1–4] The immediate implications for the clinician are severalfold:

  1. A complete assessment of pain requires screening for psychological distress, social disruption, and existential crises, to treat the pain effectively and to anticipate barriers to pain relief.
  2. Patients’ descriptions of pain that seem out of proportion to the known pathology may reflect other syndromes such as depression and existential distress.[5]
  3. Patients suffering from pain often require multidimensional interventions from supportive services such as palliative care, chaplaincy, or psychotherapy.[6]
  4. The concept of total pain does not suggest that pain is solely caused by psychological or existential distress, but that psychological and spiritual components can exacerbate or ameliorate the experience of pain. If the clinician suspects somatization, then referral for psychiatric or psychological evaluation is indicated.

Pain Mechanisms

Pain is classified on the basis of the underlying pathophysiologic mechanisms, the duration, or the description of recognizable syndromes associated with pain.[7] The three mechanisms underlying the pathophysiology of pain are:

  • Nociceptive.
  • Neuropathic.

Nociceptive pain, which may be either somatic or visceral in nature, originates with a chemical, mechanical, or thermal injury to tissue that stimulates pain receptors that transmit a signal to the central nervous system (CNS), causing the perception of pain. Pain receptors are found in somatic (e.g., cutaneous, bone) and visceral tissues. The amount of visceral sensory innervation and the diffusion of visceral pain signals within the brain explain the difficulty experienced by patients in describing or localizing visceral pain compared with somatic pain. A specific type of visceral pain is referred pain, which is explained by the commingling of nerve fibers from somatic and visceral nociceptors at the level of the spinal cord. Patients mistakenly interpret the pain as originating from the innervated somatic tissue. Visceral pain may be accompanied by autonomic signs such as sweating, pallor, or bradycardia. Somatic pain is more easily localized.

Neuropathic pain is pain caused by damage to the peripheral nervous system or the CNS (spinal cord or brain). Causes of neuropathic pain of particular relevance to cancer include chemotherapy (e.g., vinca alkaloids), infiltration of the nerve roots by tumor, or damage to nerve roots (radiculopathy) or groups of nerve roots (plexopathy) due to tumor masses or treatment complications (e.g., radiation plexopathy).[8] The pain may be evoked by stimuli or spontaneous. Patients who experience pain from nonnoxious stimuli are classified as having allodynia. Hyperalgesia connotes increased sensations of pain out of proportion to what is usually experienced.

Emotional distress may also contribute to the pain experience. Most patients with cancer and pain do not have somatic symptom disorder. However, if pain complaints appear to be disproportionate to the underlying pain stimulus, it is important to evaluate for psychological and existential distress contributing to the pain complaint, chemical coping, and substance use disorder.

Acute and Chronic Cancer Pain

Pain is often classified as either acute or chronic or by how it varies over time with terms such as breakthrough, persistent, or incidental. Acute pain is typically induced by tissue injury, begins suddenly with the injury, and diminishes over time with tissue healing. There is no definite length but, in general, acute pain resolves within 3 to 6 months.[9] The treatment of acute pain focuses on blocking nociceptive pathways while the tissue heals.

Chronic pain typically persists even after the injury has healed, although patients with chronic joint disease, for example, may have ongoing tissue damage and therefore experience chronic pain. Pain becomes chronic when it:[9]

  • Continues for more than 1 month after the healing of precipitating lesions.
  • Persists or becomes recurrent over months.
  • Results from lesions unlikely to regress or heal.

The transition from acute to chronic pain may be understood as a series of relatively discrete changes in the CNS,[9] but the genesis of chronic pain also includes clearly behavioral confounders. Chronic pain involves the activation of secondary mechanisms such as the sensitization of second-order neurons by upregulation of N-methyl-D-aspartic acid channels and alteration in microglia cytoarchitecture. Chronic pain, with its multiple factors for perpetuation, often benefits from a multidisciplinary approach to treatment.

Breakthrough Pain

In caring for patients with pain, breakthrough pain is distinguished from background pain.[10,11] Breakthrough pain is a transitory increase or flare of pain in the setting of relatively well-controlled acute or chronic pain.[12] Incident pain is a type of breakthrough pain related to certain often-defined activities or factors such as movement increasing vertebral body pain from metastatic disease. It is often difficult to treat such pain effectively because of its episodic nature.[13] In one study, 75% of patients experienced breakthrough pain; 30% of this pain was incidental, 26% was nonincidental, 16% was caused by end-of-dose failure, and the rest had mixed etiologies.[14]

References
  1. Richmond C: Dame Cicely Saunders. Br Med J 331 (7510): 238, 2005. Also available online. Last accessed Feb. 9, 2024.
  2. Mehta A, Chan LS: Understanding of the concept of “total pain”: a prerequisite for pain control. J Hosp Palliat Nurs 10 (1): 26-32, 2008.
  3. Syrjala KL, Jensen MP, Mendoza ME, et al.: Psychological and behavioral approaches to cancer pain management. J Clin Oncol 32 (16): 1703-11, 2014. [PUBMED Abstract]
  4. Merskey H, Bogduk N, eds.: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. IASP Press, 1994. Also available online. Last accessed Feb. 9, 2024.
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  6. Wachholtz A, Makowski S: Spiritual dimensions of pain and suffering. In: Moore RJ, ed.: Handbook of Pain and Palliative Care: Biobehavioral Approaches for the Life Course. Springer, 2013, pp 697-713.
  7. Chang VT, Janjan N, Jain S, et al.: Update in cancer pain syndromes. J Palliat Med 9 (6): 1414-34, 2006. [PUBMED Abstract]
  8. Dworkin RH, Backonja M, Rowbotham MC, et al.: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 60 (11): 1524-34, 2003. [PUBMED Abstract]
  9. Voscopoulos C, Lema M: When does acute pain become chronic? Br J Anaesth 105 (Suppl 1): i69-85, 2010. [PUBMED Abstract]
  10. Portenoy RK, Hagen NA: Breakthrough pain: definition, prevalence and characteristics. Pain 41 (3): 273-81, 1990. [PUBMED Abstract]
  11. Narayana A, Katz N, Shillington AC, et al.: National Breakthrough Pain Study: prevalence, characteristics, and associations with health outcomes. Pain 156 (2): 252-9, 2015. [PUBMED Abstract]
  12. Caraceni A, Martini C, Zecca E, et al.: Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med 18 (3): 177-83, 2004. [PUBMED Abstract]
  13. Mercadante S: Managing difficult pain conditions in the cancer patient. Curr Pain Headache Rep 18 (2): 395, 2014. [PUBMED Abstract]
  14. Gutgsell T, Walsh D, Zhukovsky DS, et al.: A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. Am J Hosp Palliat Care 20 (2): 140-8, 2003 Mar-Apr. [PUBMED Abstract]

Pain Assessment

Patient-Reported Outcomes

Effective pain treatment begins with screening at every visit and a thorough assessment if pain is present. Patient self-report is the standard of care for evaluating pain.[1]

Many tools have been developed to quantify the intensity of pain. The most commonly used tools include the following:

  • Numerical rating scale (0–10: 0 = no pain, 10 = worst pain imaginable).
  • Categorical scale (none, mild, moderate, severe).
  • Visual analog scale (0–100 mm: 0 mm = no pain, 100 mm = worst pain imaginable).

Multidimensional pain assessment tools such as the McGill Pain Questionnaire, the Brief Pain Inventory,[2] and the PROMIS-PI (Patient-Reported Outcomes Measurement Information System—Pain Interference) [3] have been developed to evaluate pain and its interference with daily functions. Although these tools are important, they may be best applied in the research setting, given their complexity and significant time requirements.

Pain assessment tools have been developed for special populations such as children and those with cognitive impairment. For more information, see the Special Considerations section.

Pain intensity may be assessed for different time frames, such as “now,” “last 24 hours,” or “last week.” In addition to the average pain intensity, the worst or lowest intensity may be assessed. Evaluation of pain intensity at each visit would allow clinicians to monitor for changes and treatment response. Pain intensity scales can also be used to develop a personalized pain goal (PPG).[4] A PPG is a patient’s self-reported pain management goal on a scale of 0 to 10 and is used to identify the maximum pain intensity that the patient considers tolerable.[5] The PPG is a relatively simple tool with a sensitivity of 83% and specificity of 77% when used for measuring pain relief.[6]

Patient-reported symptoms and clinician-assessed pain reporting may not be concordant, and discrepancies in assessment or interpretation of symptoms can be important in making decisions about cancer treatment. In one study, breast cancer patients who were undergoing an exercise intervention and who received four different chemotherapy regimens (e.g., anthracycline- and paclitaxel-based regimens) were assessed for symptoms of chemotherapy-induced peripheral neuropathy (CIPN) by patient self-report (the Patient-Reported Symptom Monitoring form, a five-point symptom scale) and by clinician assessment (the Common Terminology Criteria for Adverse Events form, a five-point adverse event rating scale).[7] Patient-reported pain symptoms were compared for concordance with clinician-assessed adverse events, and there was minimal agreement (weighted Cohen kappa, 0.34) between patient-reported and clinician-assessed CIPN toxicity scores. The discrepancy between patient-reported and clinician-assessed CIPN underscores the need for both patient and clinician perspectives regarding this common and potentially disabling toxicity of chemotherapy for patients with breast cancer. Treatment changes and reduced doses of anthracycline- and paclitaxel-based regimens could be driven by the inclusion of patient-reported symptoms, which may serve as a better indicator of CIPN toxicities.

Clinician Assessment

Failure to assess pain adequately leads to undertreatment. Assessment involves both clinician observation and patient report. The goal of the initial pain assessment is to characterize the pathophysiology of the pain and to determine the intensity of the pain and its impact on the patient’s ability to function. It is important to recognize that psychosocial issues can either exacerbate or ameliorate the experience of pain.[8] These psychosocial issues cannot be easily treated through pharmacological approaches; therefore, it is critical that clinicians include these in initial and subsequent examinations of patients with pain to ensure referrals to appropriate treatment resources. Furthermore, distinct cultural components may need to be incorporated into a multidimensional assessment of pain, including how culture influences the pain experience, pain communication, and provider response to pain expression.[9–12]

Identifying the etiology of pain is important for its management. Clinicians treating patients with cancer need to recognize the common cancer pain syndromes. For more information, see the sections on Approach to Somatic Pain, Approach to Visceral Pain, and Approach to Neuropathic Pain.

Effective pain management requires close monitoring of patient response after treatment is initiated. In a review of 1,612 patients referred to an outpatient palliative care center, more than half of patients with moderate to severe pain did not show pain relief (a reduction in 2 out of 10 points or a 30% decrease on the pain scale) after the initial palliative care consultation.[13] In addition, one-third of patients with mild pain progressed to moderate to severe pain by the time of their first follow-up visit. The study also identified baseline pain intensity, fatigue, and Edmonton Symptom Assessment System symptom burden as factors predicting response.[13]

Ideally, comprehensive pain assessment includes a discussion about the patient’s goals and expectations for pain management. This conversation may lead to a fruitful discussion about balancing pain levels and other patient goals, such as mental alertness. Comprehensive pain assessment also includes pain history, pain intensity, quality of pain, and location of pain. For each pain location, the pattern of pain radiation is assessed. Also important is provider awareness of the patient’s current pain management treatment plan and how the patient has responded to treatment; this includes how adequately the current treatment plan addresses any breakthrough or episodic pain. A full assessment also reviews previously attempted pain therapies and reasons for discontinuation; other associated symptoms such as sleep difficulties, fatigue, depression, and anxiety; functional impairment; and any relevant laboratory data and diagnostic imaging. A focused physical examination includes clinical observation of pain behaviors, pain location, and functional limitations.

Psychosocial and existential factors that can affect pain are also assessed and appropriately treated. Depression and anxiety can have a large influence on the pain experience. Across many different types of pain, research has shown the importance of considering a patient’s sense of self-efficacy over their pain: low self-efficacy, or focus on solely pharmacological solutions, is likely to increase the use of pain medication.[14,15] In addition, the psychological strategy of catastrophizing, an irrational thinking pattern that the outcome of any experience will always be significantly worse than what is the most likely outcome, has consistently been shown to escalate pain. Patients who repeatedly catastrophize pain (e.g., patient reports pain higher than 10 on a 10-point scale [“My pain is a 12!”] or believes that every minor, nonspecific symptom indicates a cancer recurrence [16]) are more likely to require higher doses of medication than are patients who do not catastrophize. Catastrophizing is strongly associated with low self-efficacy and greater reliance on chemical coping strategies.[16–20] Furthermore, assessing the impact of pain on the individual’s life and associated factors that exacerbate or relieve pain can reveal how psychosocial issues are affecting the patient’s pain levels.

A pain assessment includes a review of any patient and family history of substance use and the extent of the patient’s chemical coping strategies before and since the cancer diagnosis. The extent of chemical coping strategies, including reliance on legal substances (e.g., nicotine, alcohol, and sleeping pills), may indicate a history of reliance on chemicals to alleviate distress. It can also provide the clinician with information about the patient’s nicotine use, which may affect how certain opioids may be differentially metabolized and the amount of opioids required to achieve pain control.[21] A remote history of substance use disorder can still affect current pain levels and analgesic requirements. Remote substance use may have long-term implications for pain sensitivity, even if the patient has a history of prolonged abstinence from opioid use.[22] Together, personal and family substance use can inform a risk assessment for potential abuse of medications, potential analgesic requirements, and diversion of prescriptions.

Pain Prognostic Scores

Several pain-related factors and patient-related factors predict response to pain treatment. Specifically, a high baseline pain intensity, neuropathic pain, and incident pain are often more difficult to manage.[23] Furthermore, several patient characteristics are associated with higher pain expression, higher opioid doses, and longer time to achieve pain control. These characteristics include a personal or family history of the following:

  • Illicit drug use.[24]
  • Alcoholism.[24,25]
  • Smoking.[26–28]
  • Somatization.[29]
  • Mental health issues such as depression or anxiety.[30]
  • Cognitive dysfunction.[31–33]

On the basis of these predictive factors, several risk scores have been developed to assist clinicians in clinical practice, such as the Edmonton Classification System for Cancer Pain (ECS-CP) [23,34] and the Cancer Pain Prognostic Scale (CPPS).[35]

  • The ECS-CP consists of (1) neuropathic pain, (2) incident pain, (3) psychological distress, (4) addiction, and (5) cognitive impairment. The presence of any of these factors indicates that pain may be more difficult to control. The ECS-CP has been validated in various cancer pain settings.[36]
  • The CPPS includes four variables in a formula to determine the risk score, including worst pain severity (Brief Pain Inventory), Functional Assessment of Cancer Therapy – General (FACT-G) emotional well-being, initial morphine equivalent daily dose (≤60 mg/day; >60 mg/day), and mixed pain syndrome. The CPPS score ranges from 0 to 17, with a higher score indicating a higher possibility of pain relief.

Predictive factors can help to personalize cancer pain management. Especially for patients with a poor pain prognosis, clinicians may consider discussing realistic goals for alleviating pain, focusing on function and use of multimodality interventions. Repeated or frequent escalation of analgesic doses without improvement of pain may trigger clinicians to consider an alternative approach to pain.

Special Considerations

Self-report is accepted as the gold standard of pain assessment. However, for certain vulnerable populations, such as children, those with learning disabilities, and those who are cognitively impaired, self-report may not be feasible or reliable. An awareness of cultural perceptions and reporting of pain is also useful.

Children

While adults and children older than 7 years can effectively use the numerical rating scale, younger children and those with cognitive impairment may benefit from using a pictorial scale such as the Faces Pain Scale.[37]

Cognitive impairment

Cognitive impairment may impede a person’s ability to describe pain, recall pain events, or understand the tools used to assess pain. This can lead these patients to receive more or less analgesia than appropriate.[38–40] The American Society for Pain Management Nursing’s position statement on pain assessment in the nonverbal patient includes clinical recommendations.[41] Pain assessment can be evaluated via direct observation, family/caregiver report, and evaluation of response to pain relief interventions. For patients with advanced dementia, there are tools that rely on professional caregiver assessment of pain through the observation of patient behaviors.[42–44] Although the validity and reliability of these tools have been questioned, they are often recommended for patients with advanced dementia who cannot report pain. In combination with self-report by other cognitively impaired groups, these tools can enhance pain assessment and avoid undertreatment of pain.

Cognitive impairment extends beyond patients with dementia to those with brain tumors and delirium, which are common complications of advanced cancer. In such patients, the Faces Pain Scale [45] and the Coloured Analogue Scale, [46] as well as vertical instead of horizontal orientation of scales, may be preferable to the numerical rating scales.[47]

Culture

Culture also plays a role in patients’ experience and reporting of pain. For example, in some Asian cultures, patients tend not to report pain.[9] Complaining of pain may be perceived as a sign of weakness. Individuals may hide pain from family members to avoid burdening them. For some patients, pain may have spiritual value, leading them to accept pain rather than dull the experience with medication.[48] Thus, understanding an individual patient’s spiritual and cultural background, without making assumptions, is important in approaching pain assessment.

In a cross-sectional study, the cancer pain experience of White patients was individual and independent, while that of racial and ethnic minority patients was family oriented. Minority patients received support from their families during cancer treatment, and they fought cancer for their families. The families were involved deeply in decisions related to cancer treatment and pain management.[10] Other studies indicate that Asian patients have greater barriers to pain management and display more fatalism than Western patients.[11,12]

These studies describe larger cultural responses to pain that may inform assessments or improve understanding of pain communication by providers. It should be noted that subcultural differences or individual differences within each racial and ethnic group may affect the experience or expression of pain.

References
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Pharmacological Therapies for Pain Control

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Often initiated when an individual has mild pain, acetaminophen and NSAIDs are useful in managing moderate and severe pain as adjunct agents to opioids (see Table 1 and Table 3). No single NSAID is preferred over others, and all are better than placebo for analgesia.[1] As opioid adjuncts, acetaminophen and NSAIDs have shown benefit both in improved analgesia and in decreased opioid use. These agents are used with care or perhaps avoided in older patients or those who have renal, hepatic, or cardiac disease.[1] For more information, see the Geriatric cancer patients section in Treatment of Pain in Specific Patient Populations.

While acetaminophen and NSAIDs provide analgesia on their own, a number of randomized controlled trials have reported that the addition of either agent to opioids may improve pain control and decrease opioid need in cancer patients.[2–4] However, these benefits were not consistently observed across trials.[5,6]

High-potency NSAIDs such as ketorolac and diclofenac are more studied and have shown benefit in the management of cancer pain. However, there are no comparative data with older agents to show superiority of one product over others. Prominent side effects are gastrointestinal irritation, ulcer formation, and dyspepsia. Other side effects of concern include cardiotoxicity, nephrotoxicity, hepatotoxicity, and hematologic effects.[7,8] Cyclooxygenase-2 (COX-2)–specific agents such as celecoxib may have a more favorable gastrointestinal side effect profile at a higher monetary cost.[7] Long-term safety and efficacy data remain unclear.

Table 1. Acetaminophen and Selected Nonsteroidal Anti-Inflammatory Analgesics
Drug Dosage Comments Reference(s)
COX-2 = cyclooxygenase-2; GI = gastrointestinal; IM = intramuscular; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth.
Acetaminophen <4,000 mg/d Dosed every 4 to 8 hours, depending on dose and product used. [2]
Celecoxib 200–400 mg/d COX-2 specific. Minimal antiplatelet effects compared with nonselective NSAIDs. [7]
Diclofenac 100–200 mg/d Available as immediate- and delayed/extended–release products. [9]
Ibuprofen 600–2,400 mg/d   [9]
Ketoprofen 100–300 mg/d Available as parenteral in some parts of the world, which may be preferred. [7,10]
Ketorolac 40–60 mg/d, generally dosed every 6 hours Parenteral (IV, IM) ketorolac is used ≤5 days because of concerns about GI adverse events. May also be given PO. [7]

Opioids

General principles

The use of opioids for the relief of moderate to severe cancer pain is considered necessary for most patients.[1] For more information, see Table 2 and Table 3.

  • For moderate pain, weak opioids (e.g., codeine or tramadol) or lower doses of strong opioids (e.g., morphine, oxycodone, or hydromorphone) are often administered and frequently combined with nonopioid analgesics.[1]
  • For severe pain, strong opioids are routinely used. Although no agent appears to be more effective than another, morphine is often considered the opioid of choice because of provider familiarity, broad availability, and lower cost.[1]

In one well-designed review, most individuals with moderate to severe cancer pain obtained significant pain relief from oral morphine.[11] One study has also noted that low-dose morphine (up to 30 mg orally per day) provided better analgesia than did weak opioids (codeine, tramadol).[12] A 2022 update to a Cochrane review of oxycodone for cancer-related pain concluded that there were no differences in pain intensity, pain relief, and adverse effects between oxycodone and other strong opioids, including morphine. However, based on low certainty of evidence, constipation and hallucinations occurred less often with long-acting oxycodone than with long-acting morphine.[13]

The management of acute pain begins with an immediate-release opioid formulation. Once pain is stabilized, opioid consumption is converted to a modified-release or longer-acting opioid on the basis of the patient’s previous 24-hour opioid consumption. The morphine milligram equivalent (MME) can then be used to convert to an alternative opioid, if desired. Randomized controlled trials have shown that long-acting opioids given every 12 hours provide efficacy similar to that of scheduled short-acting opioids given every 4 hours.[14,15] The dosing of long-acting opioids may lead to increased adherence. This finding is based on evidence from a cross-sectional study showing that analgesic medications taken at longer dose intervals (e.g., 8, 12, or 24 hours) were associated with increased adherence (P < .001), adjusting for pain, symptom, demographic, and setting variables in the model.[16] Use of the immediate-release product is continued for the management of breakthrough pain.[1]

During ongoing pain management, the immediate-release opioids inform the titration of long-acting medications. Rapid-acting oral, buccal, sublingual, transmucosal, rectal, and intranasal products are all acceptable for the treatment of breakthrough pain. In people who are unable to take oral medications, a subcutaneous method of delivery is as effective as the intravenous route for morphine and hydromorphone.

Table 2. Selected Opioid Analgesics
Opioid Drug Equianalgesic Dosing Comments Reference(s)
Buprenorphine No consensus. Transdermal product and sublingual available. May cause less constipation and nausea than do other opioids. [17–19]
Codeine Oral: 200 mg Maximum of 360 mg/d. Used with or without acetaminophen. [1,20]
Fentanyl Transdermal: 12 µg/h × 24 h ~ 25 mg oral morphine/day. Transmucosal: no consensus; varies by product. Delivered transdermally, transmucosally, or intravenously. Cachectic patients may have decreased absorption from transdermal patch. [20–22]
Hydrocodone Immediate release formulation with acetaminophen: 20 mg Equianalgesic dose calculations for extended-release products vary; see prescribing information. [1,23]
Hydromorphone Oral: 6-7.5 mg, IV: 1.5 mg   [10,24]
Methadone Equianalgesic ratio varies widely by dose. Used primarily for severe pain in non–opioid-naïve patients. Unusual pharmacokinetics require experienced practitioner. [1,25,26]
Morphine Oral: 30 mg, IV: 10 mg Randomized trials supporting use. First-choice opioid because of familiarity, availability, and cost. [1,20]
Oxycodone 20 mg Randomized trials supporting use. [20]
Oxymorphone 10 mg   [10]
Tapentadol 100 mg Similar to morphine, 30-40 mg. [24,27,28][Level of evidence: I]
Tramadol 150 mg ~ 25 mg oral morphine Use at <400 mg/d with or without acetaminophen. Used for moderate pain. Inhibits reuptake of norepinephrine and serotonin. Caution with concomitant antidepressant use. [24]
Table 3. Routes of Analgesic Medication Administration
Route Agent Comments Reference(s)
NSAIDs = nonsteroidal anti-inflammatory drugs.
Buccal Fentanyl Used primarily for breakthrough pain. [29]
Epidural Opioids, local anesthetics Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics. [1]
Intramuscular injection Opioids, acetaminophen, ketorolac Typically avoided because of pain from injection. [10]
Intranasal Fentanyl Onset faster than that of transmucosal fentanyl or oral morphine. Used for breakthrough pain. [29]
Intrathecal Opioids Consider if inadequate analgesia or intolerable side effects with oral or intravenous analgesics. [1]
Intravenous Most strong opioids (except oxycodone) and some NSAIDs Availability varies by world region. [10]
Oral Most opioids except fentanyl and buprenorphine Most common and preferred method of administration. [10]
Rectal Morphine, methadone Onset similar to that of oral; possibly better absorption. May be useful for pediatric and end-of-life patients. [1]
Subcutaneous Morphine, fentanyl, hydromorphone, ketoprofen, methadone Benefit similar to that of intravenous; considered an alternative if no oral capacity. [1,2,30]
Sublingual Fentanyl, buprenorphine, concentrated morphine solution, methadone Used primarily for breakthrough pain. [18,29]
Topical Lidocaine Primarily application of topical anesthetics. [10]
Transdermal Fentanyl, buprenorphine Efficacy similar to that of oral agents for moderate to severe pain in opioid-naïve patients. [1]
Transmucosal Fentanyl Used primarily for breakthrough pain. [29]

Rapid-onset fentanyl formulations

Rapid-onset opioids are developed to provide fast analgesia without using a parenteral route. Fentanyl, a synthetic opioid 50 to 100 times more potent than morphine, is available in a variety of delivery methods to offer additional options for management of breakthrough pain.[31] Along with rapid onset of action, these products avoid first-pass hepatic metabolism and intestinal digestion. For more information, see Table 4.

All rapid-acting fentanyl products are intended for use only in patients already tolerant to opioids and are not initiated in opioid-naïve patients. However, none are bioequivalent to others, making dose interchange complicated and requiring dose titration of each product individually, without regard to previous doses of another fentanyl product. The dose titration schedule is unique to each product, and it is critical that product information is reviewed individually when each product is used. The risk of addiction with these rapid-onset agents has not been elucidated. In the United States, prescription of these agents requires enrollment in the U.S. Food and Drug Administration’s (FDA’s) Risk Evaluation and Mitigation Strategies (REMS) program.

Table 4. Routes of Fentanyl Administration
Drug Starting Dose (µg) Tmax (median, minutes) Comments Evidence
DB = double blinded; PC = placebo controlled; RCT = randomized controlled trial; Tmax = time to maximum blood concentration.
Transmucosal fentanyl lozenges (Actiq, generic) 200 20–40 Lozenge on stick, rubbed against cheek. Sugar content may increase dental caries. Multiple RCTs showing benefit over placebo and oral morphine.
Fentanyl buccal tablet (Fentora) 100, 200, or 400 35–45 Absorption may be affected by mucositis. Before use, wet mouth if dry. RCT showing benefit over placebo, and open-label study showing benefit for pain rescue; more rapid than oxycodone.
Fentanyl buccal film (Onsolis) 200 60 Before use, wet mouth if dry. DB, PC, RCT showing benefit.
Fentanyl nasal spray (Lazanda) 100 15–21 Vial contains residual fentanyl when empty, requiring special disposal. Do not use with decongestant sprays. DB, PC, RCT showed benefit. Open-label RCT showed benefit over transmucosal fentanyl and oral morphine. Most rapid onset.
Fentanyl sublingual spray (Subsys) 100 40–75 Contains residual fentanyl when empty, requiring special disposal. Open-label and PC RCT showing benefit.
Fentanyl sublingual tablet (Abstral) 100 30–60 Absorption may be affected by mucositis. Before use, wet mouth if dry. Multiple PC RCTs showing benefit.

Methadone

Given the complexities related to methadone administration, it is important that this opioid be prescribed by experienced clinicians who can provide careful monitoring. Referral to a pain specialist or a palliative care team may be indicated.

Methadone is both a mu-receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. It can be given via multiple routes (oral, intravenous, subcutaneous, and rectal); has a long half-life (13 to 58 hours) and rapid onset of action; and is inexpensive, making it an attractive option for cancer pain control. Because of its NMDA properties, methadone may be particularly useful for the management of opioid-induced neurotoxicity, hyperalgesia, and neuropathic pain, although further studies are needed to confirm these theoretical benefits. Methadone is safer than other opioids for patients with renal dysfunction, given that it is minimally renally excreted. It is preferred for those with known opioid allergies because it is a synthetic opioid. Additionally, it is long acting, whether given in crushed or liquid form, an important benefit when patients require drug administration via enteral tubes. However, methadone also has several distinct disadvantages, including drug interactions, the risk of QT prolongation, and a variable equianalgesic ratio, making rotation more challenging.

Methadone is metabolized by CYP2B6, CYP2C19, CYP3A4, and CYP2D6. The principal enzyme responsible for methadone levels and drug clearance is CYP2B6.[32] CYP3A4 inducers (e.g., certain anticonvulsants and antiretroviral agents) can potentially reduce its analgesic effect.[33] In contrast, enzyme inhibitors may increase methadone’s activity, including side effects. For clinicians, the potential for significant drug-drug interactions may mean that some medications need to be replaced and that patients need extra monitoring. Furthermore, because methadone is a substrate of P-glycoprotein, medications that inhibit the activity of this transporter, such as verapamil and quinidine, may increase methadone’s bioavailability.

Methadone is associated with QT prolongation. This risk increases in patients receiving high doses (especially >100 mg/day) or with preexisting risk factors, including treatment with some anticancer agents. For patients with risk factors for QT prolongation, it is important to conduct a baseline electrocardiogram (ECG) before treatment with methadone. A follow-up ECG is recommended at 2 to 4 weeks after methadone initiation if the patient has known risk factors, with the occurrence of new risk factor(s) for all patients, and when the doses of methadone reach 30 to 40 mg/day and 100 mg/day for all patients regardless of risk, if consistent with goals of care.[32,34]

Because the equianalgesic ratio between methadone and other opioids is unpredictable, most health care professionals recommend starting at a low dose twice daily, with gradual dose escalation every 3 to 5 days or at longer intervals.[32] Short-acting opioids, not methadone, should also be available for breakthrough pain. References further describe switching from opioids to methadone.[25,26]

A systematic review has highlighted three approaches to methadone conversion in the literature.[35,36] However, the quality of the evidence was low, making it difficult to conclude which approach was superior. Rapid titration of methadone may result in delayed respiratory depression because of its long half-life.[37]

Adverse effects

Adverse effects from opioids are common and may interfere with achieving adequate pain control (see Table 5). However, not all adverse effects are caused by opioids, and other etiologies also need to be evaluated. Examples of relevant factors include the following:[38]

  • Symptoms from disease progression.
  • Comorbid health conditions.
  • Drug interactions (including adjuvant analgesics).
  • Clinical conditions such as dehydration or malnutrition.

In general, options for addressing adverse effects associated with opioids include aggressive management of the adverse effects, opioid rotation, or dose reduction. In most instances, definitive recommendations are not possible.

Table 5. Relative Prevalence of Opioid Adverse Effects by Duration of Usea
Adverse Effect Relative Prevalenceb Comments
  Acute Usec Chronic Used  
aThe reported prevalence may differ on the basis of opioid choice, dose, route, and duration of use.
bRelative prevalence: (–) absent; (+) rare; (++) less common; (+++) common.
cAcute use defined as use for ≤2 weeks, as-needed use, and upon significant dose increase.
dChronic use defined as consistent use for >2–3 months at stable doses.
Cardiovascular
Hypotension + + Mostly with intravenous opioids.
Central nervous system
Sedation +++ + More common upon opioid initiation and dose increase.[39]
Dizziness ++ + [10]
Delirium/hallucinations + + [10]
Impaired cognitive status ++ + [10]
Sleep disturbances ++ + [10]
Gastrointestinal
Nausea +++ + Slow upward dose titration reduces risk. Lower rates with hydromorphone vs. morphine.[39,40]
Vomiting ++ + [10]
Constipation +++ +++ [41]
Autonomic nervous system
Xerostomia +++ + [10]
Bladder dysfunction/urinary retention + + [10]
Respiratory
Respiratory depression + – Extremely rare if used appropriately.[39]
Dermatologic
Pruritus ++ – More common with spinal analgesia.[39]
Miscellaneous
Hyperalgesia – + Observed more commonly with opioid-induced neurotoxicity. May be more common with morphine and hydromorphone.[42]
Opioid endocrinopathy/hypogonadism – + [43,44]
Hypoglycemia + + May be observed among patients on tramadol or methadone. More common among diabetics.
Opioid-induced neurotoxicity (OIN)

OIN is a broad term used to encompass the neuropsychiatric effects that result from opioid use, including:

  • Sedation.
  • Hallucinations.
  • Delirium.
  • Myoclonus.
  • Seizures.
  • Hyperalgesia.

The mechanism behind OIN may be attributed to opioids’ anticholinergic activity, endocytosis of opioid receptors, and stimulation of N-methyl-D-aspartate receptors.[45,46] Patients are at increased risk of OIN if they are receiving an opioid with active metabolites such as morphine or codeine, are older adults, have renal dysfunction or active infection, or are dehydrated. A retrospective study was conducted in patients with advanced cancer who received palliative care consultations at the University of Texas MD Anderson Cancer Center; the researchers sought to determine the frequency of and risk factors for OIN in 390 patients who had been taking opioids for 24 hours or longer.[47] A board-certified palliative care specialist diagnosed OIN using the Edmonton Symptom Assessment Scale and the Memorial Delirium Assessment Scale. Symptoms were attributed to OIN if a patient had no past medical history of that symptom; the differential diagnosis of other causes was excluded; and/or the symptoms improved upon discontinuation, decrease, or change in opioid dose. The authors found that 15% of the patients developed at least one symptom of OIN, the most common of which was delirium (47%). The mean morphine equivalent daily dose was 106 mg in patients without OIN and 181 mg in patients with OIN. Sedation and drowsiness were common but typically transient adverse effects.

Patients who have persistent problems may benefit from opioid rotation. Methylphenidate has been proposed as an intervention to reduce opioid-induced sedation.[48,49] The effects of opioids on cognitive or psychomotor functioning are not well established. Given the incidence of sedation, caution is exercised when an opioid is initiated or when dose escalation is required. There is less evidence, however, that patients on chronic stable doses exhibit cognitive or motor impairment.[50]

Delirium is associated with opioids but is typically multifactorial in origin.[51] In one retrospective study, 80% of the delirium cases were not related to opioids.[52] For more information about managing delirium, see the Delirium section in Last Days of Life.

Hyperalgesia

In contrast to opioid tolerance, opioid-induced hyperalgesia (OIH) occurs when a patient who has been taking opioids long-term experiences paradoxical pain in regions unaffected by the original pain complaint.[42,53–56] This paradoxical pain often results in clinicians increasing doses of pain medications. OIH is also defined as “the need for increasingly high levels of opioids to maintain pain inhibition after repeated drug exposure.” OIH is a clinical phenomenon that has been differentiated from opioid tolerance in the research literature in a mouse model.[54]

The clinical relevance needs to be further studied, and this issue may be underappreciated in clinical practice.

A thorough history and physical are appropriate if OIH is suspected. Changes in pain perception and increasing opioid requirements may be caused by OIH, opioid tolerance, or disease progression. There is no standard recommendation for the diagnosis and treatment of OIH. A trial of incremental opioid dose reductions may lead to an improvement in pain from OIH. However, this may be psychologically distressing to oncology patients who require opioid treatment. Opioid rotation is a strategy frequently employed if opioid tolerance has occurred. Methadone is an ideal opioid to switch to, given its mechanism of action as an opioid receptor agonist and NMDA receptor antagonist. Given the similarities between OIH and neuropathic pain, the addition of an adjunctive medication such as pregabalin has been recommended.[42]

Respiratory depression

Opioid-induced respiratory depression may be caused by a blunting of the chemoreceptive response to carbon dioxide and oxygen levels and altered mechanical function of the lung necessary for efficient ventilation and gas exchange.[57] Opioid-induced respiratory depression may manifest through decreased respiratory rate, hypoxemia, or increases in total exhaled carbon dioxide.[58] The prevalence of respiratory depression is not known but rarely occurs with proper opioid use and titration.[59–62] The following factors contribute to opioid-induced respiratory depression:

  • Obstructive sleep apnea.
  • Obesity.
  • Concomitant sedating medications.

If respiratory depression is thought to be related to opioids (e.g., in conjunction with pinpoint pupils and sedation), naloxone, a nonselective competitive opioid antagonist, may be useful. However, careful titration should be considered because it may compromise pain control and may precipitate withdrawal in opioid-dependent individuals. Because of methadone’s long half-life, naloxone infusion may be required for respiratory depression caused by methadone. For patients receiving opioids at home, nasal naloxone is indicated, particularly for those at greatest risk of respiratory depression, or if there is a concern about misuse or accidental use by others in the household.

Nausea and vomiting

Opioid-induced nausea occurs in up to two-thirds of patients receiving opioids, and half of those patients will experience vomiting.[63] Opioids cause nausea and vomiting via enhanced vestibular sensitivity, via direct effects on the chemoreceptor trigger zone, and by causing delayed gastric emptying.[64] Antiemetics may be started up front in patients at risk of developing nausea, or instituted once symptoms occur. Tolerance to opioid-induced nausea and vomiting (OINV) may develop, and symptoms should resolve within 1 week. If symptoms persist despite treatment with antiemetics, opioid rotation can be considered, or other causes of nausea can be investigated.

OINV is treated with many of the same antiemetic drugs that are used for chemotherapy-induced nausea and vomiting. Although many antiemetic regimens have been proposed for OINV, there is no current standard.[64] The chemoreceptor trigger zone is stimulated by dopamine, serotonin, and histamine. Metoclopramide may be a particularly attractive option because of its dual antiemetic and prokinetic effects. Other dopamine antagonists such as prochlorperazine, promethazine, and olanzapine have been used to treat OINV. For patients whose nausea worsens with positional changes, a scopolamine patch has been found effective. Serotonin antagonists such as ondansetron may be used. However, they could worsen constipation among patients already taking opioids.

Constipation

Constipation is the most common adverse effect of opioid treatment, occurring in 40% to 95% of patients.[65] It can develop after a single dose of morphine, and patients generally do not develop tolerance to opioid-induced constipation. Chronic constipation can result in hemorrhoid formation, rectal pain, bowel obstruction, and fecal impaction.

Opioids cause constipation by decreasing peristalsis, which occurs by reducing gastric secretions and relaxing longitudinal muscle contractions, and results in dry, hardened stool.[66] Constipation is exacerbated by dehydration, inactivity, and comorbid conditions such as spinal cord compression. Patients are encouraged to maintain adequate hydration, increase dietary fiber intake, and exercise regularly, in addition to taking laxatives.

A scheduled stimulant laxative, such as senna, is started with opioid initiation. The addition of a stool softener offers no further benefit.[67,68] Laxatives are titrated to a goal of one unforced bowel movement every 1 to 2 days. If constipation persists despite prophylactic measures, then additional assessment of the cause and severity of constipation is performed. After obstruction and impaction are ruled out, other causes of constipation (such as hypercalcemia) are treated.

There is no evidence to recommend one laxative class over another in this setting. Appropriate drugs include the following:

  • Bisacodyl.
  • Polyethylene glycol.
  • Magnesium hydroxide.
  • Lactulose.
  • Sorbitol.
  • Magnesium citrate.

Suppositories and enemas are generally avoided in the setting of neutropenia or thrombocytopenia.

Methylnaltrexone and naloxegol are peripherally acting opioid antagonists approved for the treatment of opioid-induced constipation in patients who have had inadequate response to conventional laxative regimens. Laxatives are discontinued before peripherally acting opioid antagonists are initiated. These agents are not used if postoperative ileus or mechanical bowel obstruction is suspected.[69,70]

Of note, several combination opioid and opioid-antagonist products (e.g., oxycodone-naltrexone) are FDA approved for pain management and have the added benefit of potentially preventing opioid-induced constipation.[71] Given the limited data about these agents in cancer patients and the high cost of these agents, further data are needed.

Opioid endocrinopathy

Opioid endocrinopathy (OE) is the effect of opioids on the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis over the long term. Opioids act on opioid receptors in the hypothalamus, decreasing the release of gonadotropin-releasing hormone.[72] This results in a decreased release of luteinizing hormone and follicle-stimulating hormone, and finally a reduction of testosterone and estradiol released from the gonads. These effects occur in both men and women.[44] Patients may present with the following symptoms of hypogonadism:

  • Decreased libido.
  • Erectile dysfunction.
  • Amenorrhea or irregular menses.
  • Galactorrhea.
  • Depression.
  • Hot flashes.

Treatment for OE is not well established. One group of investigators performed a 24-week, open-label pilot study of a testosterone patch in 23 men with opioid-induced androgen deficiency and reported an improvement in androgen deficiency symptoms, sexual function, mood, depression, and hematocrit levels.[73] There was no change in opioid use. Men and women with OE may be offered hormone replacement therapy after a thorough risk-benefit discussion. Testosterone replacement is contraindicated in men with prostate cancer; estrogen replacement therapy may be contraindicated in patients with breast and ovarian cancer and has serious associated health risks.

Opioid-induced immunological changes

Opioids have immunomodulatory effects through neuroendocrine mechanisms and by direct effects on opioid receptors on immune cells.[74] Opioids can alter the development, differentiation, and function of immune cells, causing immunosuppression.[43] Different opioids cause varying effects on the immune system. In mouse and rat models, methadone is less immunosuppressive than morphine. In contrast, tramadol improves natural killer cell activity. Further research is needed to determine the true clinical significance of opioid-induced immunosuppression, such as the risk of infections.

Liver disease

The liver plays a major role in the metabolism and pharmacokinetics of opioids and most drugs. The liver produces enzymes involved in two forms of metabolism:[33]

  • Phase 1 metabolism (modification reactions, CYP).
  • Phase 2 metabolism (conjugation reactions, glucuronidation).

Methadone and fentanyl are unaffected by liver disease and are drugs of choice in patients with hepatic failure.[75,76]

Morphine, oxymorphone, and hydromorphone undergo glucuronidation exclusively. CYP2D6 metabolizes codeine, hydrocodone, and oxycodone; CYP3A4 and CYP2D6 metabolize methadone; and CYP3A4 metabolizes fentanyl.[33] Hepatic impairment affects both CYP enzymes and glucuronidation processes. Prescribing information recommends caution when prescribing opioids for patients with hepatic impairment.

In cirrhosis, the elimination half-life and peak concentrations of morphine are increased.[77] Moderate to severe liver disease increases peak levels and the area under the curve (AUC) for both oxycodone and its chief metabolite, noroxycodone.[78] Peak plasma concentrations and AUC of another active metabolite, oxymorphone, are decreased by 30% and 40%, respectively.[78]

Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6. Failure to convert oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events. Hepatic disease increases the bioavailability of oxymorphone as liver function worsens.[79]

Renal insufficiency

Renal insufficiency affects the excretion of morphine, codeine, oxycodone, hydromorphone, oxymorphone, and hydrocodone. Methadone and fentanyl are safe to use in patients with renal failure, although there is some evidence that the hepatic extraction of fentanyl is affected by uremia.[80]

When patients with renal insufficiency receive hydromorphone and morphine, both hydromorphone and morphine metabolites accumulate, with the potential to cause neuro-excitatory adverse effects. Morphine, which has a higher risk of drug and metabolite accumulation, may be used in patients with mild renal failure but requires dosing at less-frequent intervals or at a lower daily dose to provide benefit with adequate safety.[78] In patients with stage III to stage IV chronic kidney disease (glomerular filtration rate <59 mL/min), morphine may not be desirable.[78]

There are conflicting reports about the safety of hydromorphone in patients with renal failure. One case series suggests adverse effects increasing when hydromorphone is given by continuous infusion to patients with renal failure.[81] Other series suggest that it is safe to use.[82] Although renal impairment affects oxycodone more than it does morphine, there is no critical accumulation of an active metabolite that produces adverse events.[78]

Opioid rotation

Opioid rotation or switching may be needed when one of the following situations occurs:[83,84]

  • The patient is experiencing side effects beyond what can be managed with simple measures. For example, the presence of OIN (e.g., sedation, hallucinations, delirium, myoclonus, seizures, or hyperalgesia) almost always warrants opioid rotation.
  • Pain control remains suboptimal despite an active effort to titrate the opioid dose. Ideally, the patient’s opioid dose is increased to the highest tolerable level before switching occurs to avoid abandoning an opioid prematurely.
  • A switch is needed for logistical reasons, such as change in the route of administration (e.g., from intravenous to oral in preparation for discharge or from oral to transdermal due to severe odynophagia); the need to minimize toxicities after the onset of renal/hepatic failure (e.g., from morphine to fentanyl or methadone); and cost considerations (e.g., from long-acting oxycodone to methadone).

The selection of a target opioid depends on the reason for rotation. All strong opioids have similar efficacy and side-effect profiles at equianalgesic doses. Because of the lack of predictors for specific opioids, empirical trials are needed to identify the ideal opioid for a patient. If OIN is the reason for switching, it may not matter which opioid is switched to, as long as it is a different agent. Patient preference, history of opioid use, route of administration, and cost are necessary considerations before the final choice is made.

A study of opioid rotation in the outpatient palliative care setting revealed that approximately one-third of 385 consecutive patients needed an opioid rotation, mostly for uncontrolled pain (83%) and OIN (12%).[85] The success rate was 65%, with a median pain improvement of two points out of ten (minimal clinically important difference is one point).[86]

Barriers related to opioid use

The barriers to appropriate use of opioids in the treatment of cancer pain include misunderstanding or misapprehension about opioids by health care providers, patients, and society. One group of investigators surveyed 93 patients with cancer cared for in an academic practice in Australia to understand patient-level concerns about the use of opioids.[87] One-third of the patients reported high levels of pain that adversely affected activity, mood, sleep, and enjoyment of life. High percentages of patients reported concerns about addiction (76%) or side effects (67%). In addition, patients expressed concerns that the pain represented disease progression (71%), that they were distracting the doctor (49%), or that they would not be seen as a “good patient” (46%).[87] Patients with more severe pain were more likely to express concerns about side effects and were less likely to use unconventional approaches to control pain. Results were similar to those of a survey of American patients from the previous decade.[88]

Physician-perceived barriers to opioid prescribing tend to parallel those of patients.[89] For example, physicians and other health care providers have beliefs about addiction that inhibit prescribing. For some, these beliefs are informed by guidelines and data extrapolated from a noncancer population. Guidelines influence physician prescribing and, at times, may be applied to populations who are not addressed in a guideline. For instance, after the Centers for Disease Control and Prevention (CDC) updated its guideline on prescribing opioids for chronic noncancer pain in 2016, [90] the mean number of opioids prescribed by oncologists per 100 Medicare beneficiaries decreased by 22.2%, from 69.0 in 2013 to 53.7 in 2017. This effect was widespread, with decreased prescribing noted in 43 of 50 U.S. states.[91] These changes in prescribing patterns resulted in decreases in frequency, dose, and duration of opioid prescriptions for U.S. patients with cancer-related pain.[92] In a large study of Medicare patients with poor prognoses, a decrease in opioid prescribing from 2007 to 2017 was correlated with an increase in emergency department visits near the end of life. This finding raises concerns about undertreated pain in this population.[93]

Similarly, a cohort study in a pediatric population compared opioid prescription rates for 8,969 privately insured pediatric cancer survivors who were 1 year off therapy (aged ≤21 years at diagnosis) and 44,845 matched peers without cancer during the time before (7 years) and after (2 years) the CDC opioid prescribing guideline. Indicators for potential misuse were 1) high daily opioid dose (≥100 MMEs daily), 2) multiple opioid prescription overlap of 7 days or more, 3) opioid and benzodiazepine overlap of 7 days or more, or 4) opioid dose escalation (≥50% increase in monthly average MME twice per year). Relative reduction in opioid prescription rates were 36.7% in survivors versus 15.9% in peers without cancer. Relative reduction in the rate of potential misuse and substance use disorder was 65.4% in survivors and 29.9% in peers without cancer. These findings raise concerns that the guideline affected access to opioid-based strategies for pain control for pediatric patients with cancer and during survivorship.[94]

Racial inequities are also seen in opioid prescribing. They worsened between 2007 and 2019 and disproportionately affected Black men. A study evaluated 318,549 non-Hispanic White, Black, and Hispanic Medicare-covered decedents older than 65 years with poor-prognosis cancers. It demonstrated that Black and Hispanic patients were less likely to receive any opioid (Black, -4.3 percentage points, 95% Confidence Interval (CI), -4.8 to -3.6; Hispanic, -3.6 percentage points, 95% CI, -4.4 to -2.9), received lower daily doses (Black, -10.5 MMEs per day [MMED], 95% CI, -12.8 to -8.2; Hispanic, -9.1 MMED, 95% CI, -12.1 to -6.1), and lower total doses (Black, -210 MMEs, 95% CI, -293 to -207; Hispanic, -179 MMEs, 95% CI, -217 to -142). Black patients were also more likely to undergo urine drug screening (0.5 percentage points; 95% CI, 0.3–0.8). Adjustment for socioeconomic factors did not attenuate the end-of-life opioid access disparities.[95] In a study that evaluated patients with head and neck cancer who received care from 2017 to 2021, White patients were significantly more likely than non-White patients to receive a new prescription for pain (adjusted odds ratio [OR], 2.52; 95% CI, 1.09–5.86), despite no statistically significant difference in odds of pain reporting between the groups (adjusted OR, 0.97; 95% CI, 0.73–1.30).[96][Level of evidence: III]

Many states have developed prescription drug monitoring programs, and the FDA requires REMS (a risk evaluation and management strategy) for certain opioids, such as rapid-onset fentanyl products. These requirements could be an additional barrier to opioid prescribing. Other barriers include poor or limited formulary and reimbursement for opioids.

Opioids and risk of addiction

In the United States, the number of deaths from opioid overdose in 2019 was nearly 50,000, over six times greater than in 1999.[97] In 2013 alone, 2 million Americans were estimated to have either abused or been dependent on opioids, with 22,767 deaths related to prescription drug overdose. Although most cancer patients prescribed opioids are using them safely, one study estimated that up to 8% of cancer patients may be addicted to opioids.[98] Thus, it is important for clinicians treating cancer patients for pain to provide careful monitoring and to adopt safe opioid-prescribing practices.[99]

To characterize opioid use disorder (OUD) and overdose in cancer patients, a retrospective cohort study was conducted using 2007 to 2014 Surveillance, Epidemiology, and End Results (SEER) Program–Medicare data for patients with a diagnosis of stage 0 to stage III breast, prostate, or colon cancer.[100] Patients with cancer were paired with up to two matched control patients without cancer. OUD and overdose were defined using Chronic Conditions Warehouse claims–based algorithms. These algorithms included, for example, ICD-9 codes for opioid-type dependence, opioid abuse, and poisonings by opiates and related narcotics. The unadjusted rates of composite OUD and nonfatal overdose were 25.2, 27.1, 38.9, and 12.4 events per 10,000 patients in the noncancer, breast cancer, colorectal cancer, and prostate cancer groups, respectively. There was no association between cancer and OUD. Interestingly, when opioid overdose was analyzed separately from OUD, colorectal cancer survivors had 2.33 times higher odds of opioid overdose in the 12 months after cancer diagnosis, compared with matched controls.

Most patients begin opioid therapy after an acute event such as a pain crisis from cancer progression or surgery.[101] Sometimes cancer treatment and its effects will lead to increased opioid use, with approximately 10% of patients continuing to take the equivalent of 30 mg of hydrocodone per day at 1 year post–curative surgery.[102] All patients taking opioids require assessment for risk of abuse or addiction.[101] For more information, see Table 6.

Addiction is defined as continued, compulsive use of a drug despite harm. Many other conditions may be misidentified as addiction, and it is important that clinicians distinguish between the two.[103] These conditions include the following:[104,105]

  • Aberrant behavior: A behavior outside the boundaries of the agreed-on treatment plan that is established as early as possible in the doctor-patient relationship.[106]
  • Chemical coping: The use of opioids to cope with emotional distress, characterized by inappropriate and/or excessive opioid use.[105]
  • Diversion: Redirection of a prescription drug from its intended user to another individual.
  • Misuse: Inappropriate use of a drug, whether deliberate or unintentional.
  • Physical dependence: Condition in which abrupt termination of drug use causes withdrawal syndrome.
  • Pseudo-addiction: Condition characterized by behaviors such as drug hoarding that mimic addiction but are driven by a desire for pain relief; usually signals undertreated pain or anxiety that future pain will be untreated.
  • Self-medication: Use of a drug without consulting a health care professional to alleviate stressors or disorders such as depression or anxiety.
  • Substance use disorder: Maladaptive pattern of substance use leading to considerable impairment or distress.
  • Tolerance: Phenomenon in which analgesia decreases as the body grows tolerant to a given dosage of a drug, requiring an increased dose to achieve the same analgesic effect.[104]

The following aberrant behaviors may suggest addiction or abuse; further assessment is required to make the diagnosis:

  • Aggressive complaining about the need for more drugs.
  • Drug hoarding during periods of reduced symptoms.
  • Acquiring similar drugs from other medical sources.
  • Requesting specific drugs.
  • Reporting psychic effects not intended by the physician.
  • Resistance to a change in therapy associated with tolerable adverse effects accompanied by expressions of anxiety related to the return of severe symptoms.
  • Resistance to referral to a mental health professional.
  • Unapproved use of the drug to treat another symptom or use of the drug for a minor symptom (e.g., use of fentanyl for mild headache pain).
  • Unsanctioned dose escalation or other nonadherence to therapy on one or two occasions.
  • Unconfirmed multiple allergies to multiple opioids.
Table 6. Risk Mitigation Tools for Evaluating Opioid Misusea
Tool Description Comments
aAdapted from DiScala SL, Lesé MD: Chronic pain. In Murphy JE, Lee MW, eds.: Pharmacotherapy Self-Assessment Program. Book 2: CNS/Pharmacy Practice. Lenexa, Kan: American College of Clinical Pharmacy, 2015, p. 102.
Current Opioid Misuse Measure (COMM) 17-item self-assessment tool for patients Identifies aberrant behaviors; for those with chronic pain who are already on opioids.
Diagnosis, Intractability, Risk, Efficacy (DIRE) 8-item tool Determines risk of long-term opioid use in those with chronic pain; evaluates regimen efficacy.
Opioid Risk Tool (ORT) 5-item tool Predicts aberrant or drug-related behaviors.
Prescription Drug Use Questionnaire (Self-Report) (PDUQp) 31-item self-assessment tool Evaluates and predicts opioid misuse in those with chronic pain.
Pain Medication Questionnaire (PMQ) 26-item tool Evaluates risk of opioid misuse in those with chronic pain.
Screening Instrument for Substance Abuse Potential (SISAP) 5-item tool Evaluates those with history of substance use disorder and risk of opioid misuse; used in primary care setting.
Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1.0 24-item self-assessment Evaluates risk of long-term opioid therapy in those with chronic pain.
Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R) 24-item self-assessment Evaluates those already taking opioids, or those about to begin (before initiation of therapy).

Risk factors for opioid abuse include the following:[103]

  • Smoking.
  • Psychiatric disorders.
  • History of childhood sexual abuse.
  • Personal or family history of substance use disorder.

Screening tools help in risk assessment. Common tools include the following:

  • Opioid Risk Tool (ORT).[107]
  • The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R).[108]
  • The Screening Instrument for Substance Abuse Potential (SISAP).[104,109]

The choice of which tool to use depends on the type of practice. The ORT is short and useful for busy practices.[104] None of the screening tools have been validated in an oncology population.

Risk assessment determines the structure of therapy, which can range from minimal structure to more structure.[110] Highly structured opioid therapy requires the following approaches:[103]

  • Frequent visits.
  • Limit on number of pills per prescription.
  • Use of other specialists.
  • Use of urine drug testing.

Opioid agreements outline what is expected of the patient, educate about drug storage, and delineate acceptable and unacceptable behavior.[111] Patients are taught that they must safeguard their medications “like their wallets” to protect against diversion. In addition, state guidelines for chronic opioid use, state prescription monitoring, and the use of pharmacists may reduce the potential for worsening addictive behavior.[112]

Random urine drug testing is used for patients with an inadequate response to opioid therapy and those receiving opioids long term as part of a risk mitigation strategy.[113] A urine drug test demonstrating absence of prescribed opioid can be useful because it suggests either diversion or stockpiling; a urine drug test revealing concurrent use of other nonprescribed medications or illicit substances can also be informative. Because many different types of urine drug tests are available, clinicians may want to become familiar with the types and interpretation of tests available locally. Awareness of false-positive and false-negative results is crucial to accurate interpretation.[114] A clinician’s laboratory can identify the substance in question. Clinicians use urine drug testing differently, with some requiring it at the initiation of therapy, episodically, or at the transition to long-term opioid therapy. Risk assessment helps to determine frequency of urine drug testing.[113]

Pharmacological deterrence has emerged as another option designed to dissuade misuse and abuse by making it difficult to obtain euphoric effects from opioid use.[113] Creating barriers to increasing the bioavailability of opioids is one method of pharmacological deterrence. One approach is to add an opioid antagonist to the formulation.[115] Embedding opioid into a matrix that cannot be obtained by crushing or chemical extraction is another pharmacological deterrent.[116]

Adjuvant Pain Medications

Gabapentin and pregabalin

Gabapentin and pregabalin are structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) but have no effect on GABA binding. Instead, they bind to the alpha2delta-1 subunit of voltage-gated calcium channels, which may result in decreased neuronal excitability in pain-associated sensory neurons. These drugs have been widely studied in the treatment of neuropathic pain syndromes and as adjunctive agents with opioids. For more information, see the Approach to Neuropathic Pain section.

These medications may cause the following symptoms:[10,117]

  • Sedation.
  • Dizziness.
  • Peripheral edema.
  • Nausea.
  • Ataxia.
  • Dry mouth.

Gradual upward titration of gabapentin to a maximum of 3,600 mg per day and pregabalin to 300 mg per day can help with dose-dependent sedation and dizziness. In addition, starting doses of gabapentin may be given at bedtime to assist with tolerating any sedation. Doses of both agents need to be adjusted for patients with renal dysfunction.[10,117]

Venlafaxine and duloxetine

The antidepressant medications venlafaxine and duloxetine have demonstrated some efficacy in the treatment of neuropathic pain syndromes. Venlafaxine and duloxetine are serotonin and norepinephrine reuptake inhibitors (SNRIs) originally approved for depression; however, both are used off-label for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). In addition, duloxetine is indicated for musculoskeletal pain. Both serotonin and norepinephrine have important roles in analgesia.

Common dosing for duloxetine ranges from 30 mg to 60 mg per day. Side effects include the following:[118]

  • Nausea.
  • Headache.
  • Fatigue.
  • Dry mouth.
  • Constipation.

Duloxetine is avoided in patients with hepatic impairment and severe renal impairment, and it carries an increased risk of bleeding.

Venlafaxine inhibits serotonin reuptake more intensely at low doses, and norepinephrine more intensely at higher doses; higher doses may be necessary for relief of CIPN.[119]

Venlafaxine can be started at 37.5 mg, with a maximum dose of 225 mg per day. Adverse effects include nausea, vomiting, headache, somnolence, and hypertension at higher doses. These effects decrease with the use of the long-acting formulations. Venlafaxine is used with caution in patients with bipolar disorder or a history of seizures and is dose-adjusted for patients with renal or hepatic insufficiency. If the decision is made to discontinue either venlafaxine or duloxetine, a slow tapering course may help to minimize withdrawal symptoms.

Tricyclic antidepressants (TCAs)

The TCAs amitriptyline, desipramine, and nortriptyline are used to treat many neuropathic pain syndromes. These drugs enhance pain inhibitory pathways by blocking serotonin and norepinephrine reuptake.

TCAs have anticholinergic, antihistaminic, and antiadrenergic effects that result in the following:

  • Dry mouth.
  • Drowsiness.
  • Weight gain.
  • Orthostatic hypotension.

Significant drug interactions are a concern, including interactions with anticholinergics, psychoactive medications, class IC antiarrhythmics, and selective serotonin reuptake inhibitors (SSRIs). Because of these adverse effects and drug interactions, TCAs are used with caution in older patients, patients with seizure disorders, and those with preexisting cardiac disease.

Corticosteroids

There is a lack of high-quality data demonstrating the efficacy of corticosteroids in treating cancer pain. A systematic review of the literature resulted in four randomized controlled trials and concluded that there is low-grade evidence to suggest corticosteroids have moderate activity in the treatment of cancer pain.[120] A small but well-designed study showed no benefit to adding corticosteroids to opioid analgesia in the short term (7 days).[121]

Despite the lack of good evidence, corticosteroids are often used in the clinical setting. Corticosteroids (dexamethasone, methylprednisolone, and prednisone) may be used as adjuvant analgesics for cancer pain originating in bone, neuropathy, and malignant intestinal obstruction. Mechanisms of analgesic action include decreased inflammation, decreased peritumoral edema, and modulation of neural activity and plasticity.[122]

Although there is no established corticosteroid dose in this setting, recommendations range from a trial of low-dose therapy such as dexamethasone 1 mg to 2 mg or prednisone 5 mg to 10 mg once or twice daily,[123] to dexamethasone 10 mg twice daily.[124] A randomized trial demonstrated that dexamethasone (8 mg on day of radiation therapy and daily for the following 4 days) reduces the incidence of pain flares, compared with placebo.[125] For more information, see the External-Beam Radiation Therapy section.

The immediate side effects of corticosteroid use include:

  • Hyperglycemia.
  • Insomnia.
  • Immunosuppression.
  • Psychiatric disorders.

Serious long-term effects—myopathy, peptic ulceration, osteoporosis, and Cushing syndrome—encourage short-term use of corticosteroids. If taken for more than 3 weeks, corticosteroids are tapered upon improvement in pain, if possible. If corticosteroids are to be continued long term, anti-infective prophylaxis can be considered. Dexamethasone is preferred because it has reduced mineralocorticoid effects, resulting in reduced fluid retention; however, it does exhibit cytochrome P450–mediated drug interactions.

Bisphosphonates and denosumab

The bisphosphonate class of drugs inhibits osteoclastic bone resorption, decreasing bone pain and skeletal-related events associated with cancer that has metastasized to the bone. Pamidronate and zoledronic acid decrease cancer-related bone pain, decrease analgesic use, and improve quality of life in patients with bone metastases.[126–129] American Society of Clinical Oncology (ASCO) guidelines for the use of these bone-modifying agents in patients with breast cancer and myeloma specify they should be used not as monotherapy but as part of a treatment regimen that includes analgesics and nonpharmacological interventions.[130,131] Bisphosphonates can cause an acute phase reaction characterized by fever, flu-like symptoms, arthralgia, and myalgia that may last for up to 3 days after administration. Additional adverse effects include renal toxicity, electrolyte imbalances, and osteonecrosis of the jaw.[132–134] Doses are adjusted for patients with renal dysfunction.

A single dose of ibandronate 6 mg was compared with a single fraction of radiation for localized metastatic bone pain in 470 prostate cancer patients.[135] Patients were allowed to cross over if they failed to respond at 4 weeks. Pain was assessed at 4, 8, 12, 26, and 52 weeks. Pain response was not statistically different between the two groups at 4 or 12 weeks; however, a faster onset of pain response was seen in the radiation therapy group. Interestingly, patients who crossed over and received both treatments had a longer overall survival than did patients who did not cross over. The authors concluded that ibandronate provides a feasible alternative to radiation therapy for the treatment of metastatic bone pain when radiation therapy is not an option.

Denosumab is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL), prevents osteoclast precursor activation, and is primarily used in the treatment of bone metastases. A review of six trials comparing zoledronic acid with denosumab demonstrated a greater delay in time to worsening pain for denosumab (relative risk, 0.84; 95% CI, 0.77–0.91).[136]

Compared with zoledronic acid, denosumab has similar adverse effects with less nephrotoxicity and increased hypocalcemia. There is no adjustment for renal dysfunction; however, patients with a creatinine clearance lower than 30 mL/min are at a higher risk of developing hypocalcemia. Denosumab may be more convenient than zoledronic acid because it is a subcutaneous injection and not an intravenous infusion; however, it is significantly less cost-effective.[137]

Ketamine

Ketamine is an FDA-approved dissociative general anesthetic that has been used off-label in subanesthetic doses to treat opioid-refractory cancer pain. A 2012 Cochrane review of ketamine used as an adjuvant to opioids in the treatment of cancer pain concluded there is insufficient evidence to evaluate its efficacy in this setting.[138]

Lack of demonstrated clinical benefit, significant adverse events, and CYP3A4-associated drug interactions limit ketamine’s utility in the treatment of cancer pain. It is an NMDA receptor antagonist that, at low doses, produces analgesia, modulates central sensitization, and circumvents opioid tolerance. However, a randomized placebo-controlled trial of subcutaneous ketamine in patients with chronic uncontrolled cancer pain failed to show a net clinical benefit when ketamine was added to the patients’ opioid regimen.[139] Adverse drug reactions include the following:

  • Hypertension.
  • Tachycardia.
  • Psychotomimetic effects.
  • Increased intracranial and intraocular pressure.
  • Sedation.
  • Delirium.
  • Impaired bladder function.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  107. Webster LR, Webster RM: Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 6 (6): 432-42, 2005 Nov-Dec. [PUBMED Abstract]
  108. Butler SF, Fernandez K, Benoit C, et al.: Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain 9 (4): 360-72, 2008. [PUBMED Abstract]
  109. Coambs RB, Jarry JL, Santhiapillai AC, et al.: The SISAP: a new screening instrument for identifying potential opioid abusers in the management of chronic nonmalignant pain within general medical practice. Pain Res Manag 1 (3): 155-62, 1996.
  110. Paice JA, Portenoy R, Lacchetti C, et al.: Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 34 (27): 3325-45, 2016. [PUBMED Abstract]
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  112. Wiedemer NL, Harden PS, Arndt IO, et al.: The opioid renewal clinic: a primary care, managed approach to opioid therapy in chronic pain patients at risk for substance abuse. Pain Med 8 (7): 573-84, 2007 Oct-Nov. [PUBMED Abstract]
  113. Gourlay DL, Heit HA, Almahrezi A: Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med 6 (2): 107-12, 2005 Mar-Apr. [PUBMED Abstract]
  114. Arthur JA: Urine Drug Testing in Cancer Pain Management. Oncologist 25 (2): 99-104, 2020. [PUBMED Abstract]
  115. Chindalore VL, Craven RA, Yu KP, et al.: Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex. J Pain 6 (6): 392-9, 2005. [PUBMED Abstract]
  116. Setnik B, Roland CL, Cleveland JM, et al.: The abuse potential of Remoxy(®), an extended-release formulation of oxycodone, compared with immediate- and extended-release oxycodone. Pain Med 12 (4): 618-31, 2011. [PUBMED Abstract]
  117. Dworkin RH, O’Connor AB, Audette J, et al.: Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85 (3 Suppl): S3-14, 2010. [PUBMED Abstract]
  118. Pachman DR, Watson JC, Loprinzi CL: Therapeutic strategies for cancer treatment related peripheral neuropathies. Curr Treat Options Oncol 15 (4): 567-80, 2014. [PUBMED Abstract]
  119. Pachman DR, Barton DL, Watson JC, et al.: Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 90 (3): 377-87, 2011. [PUBMED Abstract]
  120. Paulsen Ø, Aass N, Kaasa S, et al.: Do corticosteroids provide analgesic effects in cancer patients? A systematic literature review. J Pain Symptom Manage 46 (1): 96-105, 2013. [PUBMED Abstract]
  121. Paulsen O, Klepstad P, Rosland JH, et al.: Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial. J Clin Oncol 32 (29): 3221-8, 2014. [PUBMED Abstract]
  122. Leppert W, Buss T: The role of corticosteroids in the treatment of pain in cancer patients. Curr Pain Headache Rep 16 (4): 307-13, 2012. [PUBMED Abstract]
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  125. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015. [PUBMED Abstract]
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Modalities for Pain Control: Other Approaches

Pain Procedures

While pharmacological therapy using the World Health Organization (WHO) guidelines effectively manages most cancer pain, approximately 10% to 20% of patients will have refractory pain or excessive side effects.[1] For patients with refractory pain or specific regional pain syndromes, an interventional approach to treating pain has been proposed as the fourth step on the WHO pain relief ladder. Some common interventions and their evidence of benefit are discussed below.

Nerve blocks

The celiac plexus block, used primarily for patients with upper abdominal pain from pancreatic cancer, is the most commonly employed neurolytic blockade of the sympathetic axis, followed by the superior hypogastric plexus block and the ganglion of impar block for patients with lower abdominal or pelvic pain. Traditionally, the autonomic neural blockade was reserved for patients with inadequate response to oral opioids, but some researchers have suggested that the intervention—which is associated with decreased pain, reduced opioid consumption, improved performance status, and few complications—is considered a first-line approach.[2,3]

For patients with regional pain, a peripheral nerve block infusing a local anesthetic can achieve local pain control. This approach can be applied to any peripheral nerve, including the femoral, sciatic, paravertebral, brachial plexus, and interpleural nerves.[4]

Neuroaxial delivery of analgesia

When patients have pain that persists despite high doses of opioids and other analgesics or have intolerable side effects to oral opioids—such as delirium, sedation, or nausea—an alternative route of delivery may be considered. Compared with intravenous administration of opioids, epidural and intrathecal routes of delivery are 10 and 100 times more potent, respectively. Such routes of delivery allow high doses of analgesics to be administered with less systemic absorption and fewer side effects.[5]

One study that randomly assigned patients to receive either an implantable drug delivery system or comprehensive medical management found that patients receiving the analgesic through the implantable pump had less pain, less toxicity, and longer survival at 6 months.[6] While the survival benefit did not persist in other studies, the intrathecal pump may be an option for selected patients with refractory pain and a life expectancy longer than 3 months.[7] However, intrathecal pumps may make it difficult for patients to access hospice care because of care needs and cost issues, and they cannot effectively treat pain that is predominantly related to psychological distress.[8] For patients with shorter life expectancies, placement of an epidural catheter may be a safe and effective technique.[4]

Cordotomy

Cordotomy is reserved for pain refractory to other approaches and is done less commonly today. It is most effective in treating unilateral somatic pain from the torso to the lower extremities. The available literature suggests a high rate of efficacy, with 60% to 80% complete pain relief immediately after the procedure, falling to 50% at 12 months. Cordotomy is generally reserved for patients considered to be in the last 2 years of life, with pain refractory to other approaches, and may be done via the open route or the percutaneous route.[9–11]

For patients with either regional pain syndromes or pain refractory to escalating systemic medications, the cancer clinician may consult with a pain specialist or neurosurgeon to consider an interventional approach to pain control.

Palliative Care Referral

Palliative care, which is specialized medical care for people with serious illnesses with the goal to maximize quality of life (QOL) for both patients and families, can provide expert assessment and management of pain and other nonpain symptoms. Palliative care providers work in interdisciplinary teams that include the following:

  • Physicians.
  • Nurses.
  • Mental health specialists.
  • Social workers.
  • Chaplains.
  • Pharmacists.
  • Dieticians.

For patients with refractory pain, prominent nonpain symptoms, or intense psychosocial distress, a referral to palliative care may be appropriate, where available. Many palliative care teams now call themselves supportive care teams because this term is more acceptable to many referring providers and to some patients and families.[12,13]

Palliative care specialists may also help manage patients with multiple comorbidities, those requiring higher doses of opioids, and those with a history of substance use disorder or complex psychosocial dynamics that can complicate the management of pain and adherence to recommended medications. Most palliative care specialists have experience using methadone for pain.

The role of specialty palliative care integrated into cancer care has been well studied, with studies showing that early integration of specialty palliative care into cancer care reduces symptom burden and enhances QOL for both patients and families [14–17] and may prolong life.[14] For more information, see Planning the Transition to End-of-Life Care in Advanced Cancer.

External-Beam Radiation Therapy

Palliative radiation therapy represents an effective modality for pain related to advanced cancer. Pain related to bone metastases, skin lesions, or isolated tumor lesions may be relieved by a short course of radiation therapy. Patient selection can be important regarding the likelihood of benefit from radiation therapy.[18] In one study, patients with hematologic tumors, a neuropathic component of the index pain, and no previous treatment with opioid analgesics before radiation therapy were more likely to experience pain palliation after radiation therapy.[19]

For bone metastases, radiation is often delivered as 8 Gy in a single fraction, 20 Gy in five fractions, 24 Gy in six fractions, or 30 Gy in ten fractions. A Cochrane review that included 11 randomized trials consisting of 3,435 patients showed that single-fraction radiation therapy for bone pain provided a similar overall response rate (60% vs. 59%) and complete response rate (34% vs. 32%), compared with multifraction radiation therapy.[20] However, patients who received single-fraction radiation therapy had a higher rate of re-treatment (22% vs. 7%) and a higher rate of pathological fracture (3% vs. 1.6%).[20] This finding was consistent with other systematic reviews.[21] In the Dutch Bone Metastasis Study, the average time to first pain relief was 3 weeks; the peak effect was achieved in 4 to 6 weeks; and the mean duration of response was approximately 30 weeks.[22,23] Single-fraction radiation has several potential advantages:

  • Greater convenience.
  • Lower cost.
  • Less breakthrough pain associated with transportation to the radiation facility and with getting on and off the radiation table.

A study published in 2019 evaluated a higher-dosage (Gy) single-fraction stereotactic body radiation therapy (SBRT) versus multifraction radiation therapy (MFRT), in which patients with primarily nonspine bone metastases received either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in ten fractions. This randomized phase II trial demonstrated improved pain at 2 weeks, 3 months, and 9 months, without differences in treatment-related toxicity and with no increase with re-treatment rates that had been seen in previous single-fraction studies, done largely with 8 Gy. Patients who received the higher-dose SBRT had improved 1- and 2-year survival rates. The authors concluded that the higher dose of single-fraction SBRT is safe and suggested that this could become the standard of care, if confirmed in phase III studies.[24][Level of evidence: I]

Re-irradiation may be considered for selected patients who derive no or partial pain relief with first-time radiation therapy, or who develop worsening pain after an initial response. Re-irradiation typically occurs at least 4 weeks after the first radiation treatment. A systematic review that examined re-irradiation for bone metastases included 15 studies and reported a complete response rate of 20% and a partial response rate of 50%.[25] Re-irradiation was generally well tolerated.[25] In a secondary analysis of the National Cancer Institute of Canada (NCIC) Clinical Trials Group Symptom Control Trial SC.20, which examined outcomes of 847 patients who underwent palliative re-irradiation of painful bone metastases, the team found no differences in pain relief or side effects across age or gender demographics. Women and younger patients reported greater improvements in QOL.[26] Serious adverse effects such as spinal cord compression and pathological fracture were infrequent (<3%). A randomized controlled trial compared a single fraction (8 Gy) with multiple fractions (20 Gy over 5 days) of re-irradiation and found similar response rates at 2 months in an intention-to-treat analysis (28% vs. 32%; P = .02).[27]

A potential side effect of palliative radiation for painful bone metastases is a temporary increase in pain level, i.e., a pain flare. Pain flares occur in about 40% of patients and may be quite distressing. One study [28] randomly assigned 298 patients, who were scheduled to receive a single 8-Gy dose of radiation, to receive either placebo or dexamethasone 8 mg on days 0 to 4. Fewer patients in the dexamethasone group experienced pain flares (26% vs. 35%; P = .05). Potentially serious hyperglycemia was seen in only two patients in the dexamethasone group. The study supports the use of prophylactic dexamethasone in this setting.

In a secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, the authors investigated pain and QOL at days 10 and 42 after radiation therapy, with the aim of determining whether there are differences in QOL between responders and nonresponders.[29] Overall, 40% of patients experienced pain reduction and improvement in QOL at day 10, with continued improvement in QOL at day 42. Compared with baseline, patients responding to radiation experienced significantly increased improvements in the physical, emotional, and global domains of the day-42 QOL tool.

Radionuclides

Patients with multiple sites of symptomatic osteoblastic bone metastases may consider radionuclides such as strontium chloride Sr 89 or samarium Sm 153 (153Sm), which are beta-emitters. Two double-blind randomized trials support the superiority of 153Sm over placebo in providing pain control and reducing analgesic use.[30,31] The overall response varies between 30% and 80%, with onset of pain relief within the first week; some patients report a long-lasting benefit (up to 18 months). The most common toxicities are pain flare and cytopenias. Pain flare typically occurs in approximately 10% of patients within the first 24 to 48 hours of administration and may be treated with corticosteroids or opioids.[32] Leukopenia and thrombocytopenia are sometimes seen, with a nadir of 4 weeks posttreatment and recovery by 8 weeks. Contraindications to radionuclide therapy include a poor performance status (Karnofsky Performance Status score <50%) and a short life expectancy (<3 months).

Radium Ra 223-dichloride (223Ra-dichloride) (an alpha-emitter) is approved for use in patients with castration-resistant prostate cancer. A phase III randomized trial compared 223Ra-dichloride with placebo in a 2:1 ratio. Among the 921 symptomatic patients enrolled, those who received 223Ra-dichloride had a prolonged time to first symptomatic skeletal event (15.6 months vs. 9.8 months, P < .0001), in addition to prolonged overall survival (14.9 months vs. 11.3 months, P < .001).[33]

Physical Medicine and Rehabilitation

Patients with cancer and pain may experience loss of strength, mobility, and, ultimately, functional status secondary to the cause of pain, (e.g., vertebral metastases, incident pain, and chronic nonmalignant pain). Therefore, pain and functional status may improve with physical or occupational therapy, treatments for strengthening and stretching, and the use of assistive devices.[34] Referral to a physiatrist (a physician who specializes in rehabilitation medicine) who could create a comprehensive plan may benefit the patient. In addition, some physiatrists practice interventional pain medicine.

Integrative Therapy

Patients with cancer frequently use complementary or alternative medicines or interventions (CAM).[35] One of the stated benefits of CAM is pain relief. However, a meta-analysis of multi-institutional, randomized, controlled trials for cancer-related pain concluded that methodological flaws hampered interpretation of the few available studies. There were brief positive effects in favor of CAM for acupuncture, support groups, hypnosis, and herbal supplements.[36] For more information, see the summaries on Integrative, Alternative, and Complementary Therapies.

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General Approaches to Pain Treatment

Decision-Making Approach

Pain management varies widely in complexity. The decision-making process involves a careful consideration of many patient-related and pain-related factors. These may include, but are not limited to the following:

  • Pain mechanism.
  • Pain expression.
  • Previous treatments.
  • Available options.
  • Prognosis.

Recognition of specific pain syndromes can be useful in guiding management.

Approach to Somatic Pain

Damage and/or inflammation involving the muscles, skin, joints, connective tissue, or bones can lead to activation of the nociceptive pathways that result in somatic pain. This type of pain is often well localized; may be described as sharp, achy, throbbing, and/or stabbing in nature; and often worsens with movement. It can often be managed with acetaminophen, anti-inflammatories, and opioids. Bone pain related to metastases is particularly common in cancer patients and is discussed below in more detail.

Bone pain

Bone pain due to metastatic disease is one of the most common causes of pain in cancer patients.[1,2] Bone is highly innervated tissue with receptors sensitive to mechanical damage.[3] The entrapment of nerve fibers in the collapsing bony matrix caused by increased osteoclastic activity and the release of inflammatory cytokines by cancer cells and immune cells are also central to the pathophysiology of bone pain.[3] Patients typically describe the pain as continuous, deep, and throbbing, with brief episodes of more-severe pain often precipitated by movement (i.e., a type of incident pain).

Most patients will require morphine or an equivalent opioid for adequate pain relief, although incident pain is less responsive. Adjunctive agents such as nonsteroidal anti-inflammatory drugs and corticosteroids are often prescribed and appear moderately effective and safe.[4]

In addition to providing analgesia, the clinician introduces treatments designed to prevent further weakening of skeletal integrity, which may lead to loss of functional status or further pain. Bone-targeting agents such as the bisphosphonates (zoledronic acid or pamidronate) or denosumab have been shown to reduce future skeletal-related events and to reduce the likelihood of increased pain or increased use of opioids in patients with advanced cancer.[5] For more information, see the Bisphosphonates and denosumab section.

Palliative radiation therapy produces complete or partial pain relief in up to 80% of treated patients; the median duration of relief exceeds 6 months.[6] For more information, see the External-Beam Radiation Therapy section.

Finally, orthopedic consultation is frequently necessary to determine whether operative intervention is required to prevent and/or treat pathological fractures.

Approach to Visceral Pain

Visceral pain is a type of nociceptive pain that originates in nociceptors innervating visceral organs. Several features of visceral pain inform the therapeutic approach:

  1. Not all internal organs have nociceptors. Typically, the hollow viscera (stomach, bowel, bladder, and ureters) are innervated and respond to mechanical-, inflammation-, and chemical-induced damage. For example, sensations originating from the liver or spleen are typically caused by distension of the capsule.
  2. There is a limited correlation between the degree of visceral injury and the intensity of the perceived pain.[7]
  3. The source of visceral pain is often difficult to localize. Referred pain may be perceived as remote from the actual affected organ (e.g., shoulder pain with splenic injury).
  4. In the phenomenon of sensitization, the normal activity of an organ is perceived as painful, such as stomach inflammation causing hyperawareness or hyperalgesia-related peristalsis of the stomach.

Opioids remain the core treatment for severe or distressing visceral pain.[8] Also important are radiographic studies to look for underlying causes that may be amendable to other interventions (e.g., bowel obstruction).

Approach to Neuropathic Pain

Pain with features suggestive of neuropathic pain is common among patients with cancer and can have substantial negative consequences. One study of 1,051 patients with cancer found that 17% had neuropathic pain. These patients reported worse physical, cognitive, and social functioning than did those with nociceptive pain; were on more analgesic medications and higher doses of opioids; and had a worse performance status.[9] Neuropathic pain is considered less responsive to opioids. Multiple therapeutic options instead of or in addition to opioids have been studied. Most of these studies were conducted in patients with nonmalignant sources of neuropathic pain and may not be applicable to patients with cancer with different etiologies for their neuropathic pain.

Gabapentin can be used as monotherapy in the first-line setting for neuropathic pain or in combination therapy if opioids, tricyclic antidepressants (TCAs), or other agents do not provide adequate relief. Gabapentin improved analgesia when added to opioids for uncontrolled cancer-related neuropathic pain.[10,11] When gabapentin was used adjuvantly to an opioid regimen, improvement in pain control was seen within 4 to 8 days.[12] In an open-label trial of pregabalin compared with fentanyl in 120 cancer patients with “definite” neuropathic pain, patients on pregabalin were twice as likely (73.3%) than those on fentanyl (36.7%) to report 30% or more reduction in pain, as measured by a visual analog scale (VAS).[13] Compared with monotherapy with amitriptyline, gabapentin, or placebo, pregabalin use resulted in a significant decrease in pain score when studied in neuropathic cancer pain.[14] In a randomized clinical trial of patients with head and neck cancer who were undergoing radiation therapy, pregabalin was shown to improve radiation therapy–related neuropathic pain, mood, and quality of life (QOL), with good tolerability.[15]

Notably, in a systemic review of neuropathic pain that included mostly patients with a nonmalignant source of neuropathic pain, the effect of gabapentin and pregabalin appeared less robust.[16] Data comparing gabapentin or pregabalin directly with TCAs and serotonin–norepinephrine reuptake inhibitors (SNRIs) are limited, especially in patients with cancer. Efficacy of TCAs and SNRIs appears to be comparable and, in some cases, superior to gabapentin or pregabalin. For more information, see the Chemotherapy-induced peripheral neuropathy (CIPN) section. Because of concerns about side effects and drug-drug interactions, many practitioners tend to start with gabapentin or pregabalin as first-line treatment for neuropathic pain. However, as noted below, certain neuropathic syndromes may be less responsive to these agents. For more information, see the sections on Postthoracotomy pain syndrome and Chemotherapy-induced peripheral neuropathy (CIPN). Studies have also examined the use of lidocaine patches, tramadol, topically applied capsaicin, and botulinum toxin A for use in patients with neuropathic pain [16] with inconclusive results.

Postmastectomy pain syndrome

Rates of postmastectomy pain range between 25% and 33%,[17–20] making this a common complication. Women with postmastectomy pain note more role limitations due to physical, emotional, and mental health issues.[17] Associations of postmastectomy pain with extent of surgery, radiation therapy, and chemotherapy are inconsistent across studies. One cross-sectional study found associations between postmastectomy pain and psychosocial factors such as depression, anxiety, somatization, and catastrophizing.[18,20]

A number of small studies have examined the effect of an anesthetic administered intraoperatively or immediately postoperatively, with varying results;[21] one group found a decrease in pain during the infusion but no benefits after the infusion until 12 months.[22,23] The use of venlafaxine or gabapentin for 10 days [24] or pregabalin for 7 days [25] starting 1 day before surgery may decrease postmastectomy pain, but confirmatory studies are needed.

Postthoracotomy pain syndrome

Defined as pain occurring 2 months after thoracotomy, postthoracotomy pain syndrome occurs in approximately 50% of patients and may be underreported and undertreated. The pain is thought to be related to damage to the intercostal nerve during surgery and from postoperative drainage via chest tubes. The pain includes both neuropathic and nonneuropathic components.[26]

Opioid and nonopioid analgesics are part of the standard approach to treatment. Several approaches in the immediate postoperative period are being investigated. An open-label noncontrolled study of 5% lidocaine patches showed improvement in pain scores 1 month postoperatively.[27] A small randomized trial of transcutaneous electrical nerve stimulation demonstrated decreased pain and reduced use of morphine and nonopioid analgesia in the immediate postoperative period.[28] Patients randomly assigned to receive intraoperative cryoanalgesia versus placebo were found to have less pain at time points up to 60 days postoperatively and reduced analgesic use in the first 3 days.[29] Further work is needed to confirm these results. In a randomized, double-blinded, placebo-controlled study of gabapentin started preoperatively and titrated over 5 days postoperatively, gabapentin failed to show benefit.[30]

Chemotherapy-induced peripheral neuropathy (CIPN)

Overview

Peripheral neuropathy is a common toxic effect of chemotherapy and is predominantly a sensory neuropathy. Patients report numbness and tingling in a stocking-and-glove distribution. CIPN is most commonly associated with the following:[31]

  • Platinum compounds (e.g., oxaliplatin, cisplatin, and carboplatin, in descending order of severity).
  • Taxanes (e.g., paclitaxel, docetaxel, and cabazitaxel).
  • Thalidomide.
  • Proteasome inhibitor (e.g., bortezomib, carfilzomib, and ixazomib).
  • Vinca alkaloids.

Other agents, including ixabepilone, lenalidomide, and pomalidomide, are common sources of CIPN. With any of these agents, CIPN may limit the dose of chemotherapy delivered, which may affect the outcomes of treatment.[31] In one series of women treated with docetaxel, approximately one in four reported CIPN.[32] Although CIPN often improves after discontinuation or completion of chemotherapy, symptoms can linger for years for some patients, especially those treated with taxanes, with one study demonstrating a median 6.5-year duration of symptoms after diagnosis.[33,34] Newer immunotherapies, such as pembrolizumab and nivolumab, can produce peripheral neuropathies. The prevalence may become clear as more patients are treated with these agents.[35]

In two studies of women with breast cancer, peripheral neuropathy correlated negatively with QOL.[36][Level of evidence: II]; [37] The effect of a docetaxel regimen and patient characteristics on peripheral neuropathy and QOL was evaluated in a substudy of the NASBP B-30 trial.[37] The B-30 trial randomly assigned women with node-positive, early-stage breast cancer to one of three regimens: four cycles of doxorubicin plus cyclophosphamide every three weeks, followed by four cycles of docetaxel 100 mg/m2 (AC→T); four cycles of doxorubicin plus docetaxel 60 to 75 mg/m2; or four cycles of doxorubicin plus cyclophosphamide plus docetaxel 60 to 75 mg/m2. Overall, 41.9% of patients reported peripheral neuropathy 24 months after beginning treatment, with 10.3% reporting a severe symptom (“quite a bit”/“very much”/“bother” level). Treatment with AC→T, the regimen with the highest cumulative dose of docetaxel, resulted in increased severity of peripheral neuropathy compared with the other two regimens. Women who reported worse peripheral neuropathy symptoms had a statistically significant decreased QOL.

Preventing and reducing risk of CIPN

In 2020, the American Society of Clinical Oncology released a guideline update on the prevention and management of CIPN. At the time, there were no studies whose outcomes supported the recommendation of any neuropathy-preventive agents. A previously documented benefit of venlafaxine was refuted in a subsequent randomized, placebo-controlled, double-blind study, in which 50 patients were randomly assigned to receive venlafaxine extended-release 37.5 mg twice daily or a placebo. The study demonstrated no significant benefit for those who received venlafaxine.[38]

It is recommended that clinicians assess the risks and benefits of agents known to cause CIPN among patients with underlying neuropathy and with conditions that predispose to neuropathy. These conditions include the following:[39,40]

  • Older age.
  • Obesity.
  • Lower physical activity.
  • Diabetes.
  • Longer planned duration of treatment.
  • A family or personal history of hereditary peripheral neuropathy.
  • Symptom burden.
  • Alcohol intake.

The risk of long-term CIPN has also been documented. At 24 months after treatment initiation for early-stage breast cancer, women with the following characteristics were at an increased risk of continued peripheral neuropathy:[37]

  • Preexisting peripheral neuropathy.
  • Older age.
  • Obesity.
  • Mastectomy.
  • Greater number of positive lymph nodes.

In a genome-wide association study, genetically determined African American ancestry was the most significant predictor of taxane-induced peripheral neuropathy.[41] It should be noted that the impact of risk-factor profiles may differ between racial and ethnic groups, as reported in one observational study of African American patients.[42] Eligible African American cancer survivors were surveyed to determine if there was an association between nongenetic risk factors and comorbidities with CIPN. Patients with CIPN were more likely to report hypertension, hypercholesterolemia, depression, diabetes, or increased body mass index (BMI). In contrast, alcohol consumption and tobacco use were not associated with increased risk of CIPN.

Treatment modalities for CIPN
Pharmacological treatments

American Society of Clinical Oncology (ASCO) guidelines [40,43] recommend against the use of many commonly prescribed agents for the treatment of existing CIPN. The exception is duloxetine because it is the only agent whose efficacy in treating CIPN is evidence based.[44] One large phase III trial identified an average decrease of 0.73 in the pain scores of patients who titrated up to 60 mg of duloxetine daily, when compared with placebo. Patients also had improvements in daily functioning and QOL.[44] Some argue that, while statistically significant, the difference of less than 1 (0.73) on a pain scale of 0 to 10 may not be clinically important.

Gabapentin failed to provide a benefit in CIPN when used as monotherapy in a randomized, double-blind, placebo-controlled trial.[44,45] The Cancer and Leukemia Group B prospective observational study evaluated 2,450 patients with stage III colon cancer. Increased severity of oxaliplatin-induced peripheral neuropathy (OIPN) may be linked to higher BMI, lower physical activity, diabetes mellitus, and a longer planned duration of treatment. Celecoxib and vitamin B6 intake did not attenuate OIPN.[46]

Evidence of the efficacy of nortriptyline and amitriptyline in CIPN is limited to small and frequently underpowered trials with mixed results.[47–49] Despite inconclusive trials, the authors suggested that a trial of TCAs, gabapentin, and topical baclofen/amitriptyline/ketamine may be reasonable in light of evidence supporting the benefit of these agents in other types of neuropathy and the relative lack of effective alternatives in this setting.[50]

Complementary and integrative therapies

Importantly, a large, randomized, multicenter, double-blind, placebo-controlled trial comparing the use of acetyl-L-carnitine with placebo in 409 women receiving taxane-based chemotherapy for breast cancer showed worsened CIPN. This worsening persisted over 2 years.[51]

Nonpharmacological treatments
Acupuncture

Studies of acupuncture for CIPN have been reported. For more information, see the Chemotherapy-induced peripheral neuropathy section in Acupuncture.

Scrambler therapy

Scrambler therapy is the application of electrical currents to discrete areas of the body as guided by the patient’s report of pain. The therapy is usually applied in ten consecutive sessions, although guidelines permit the skipping of weekend days. The technique is operator dependent, given the importance of identifying the area to treat and the application of the electrical current through five electrodes (referred to as artificial neurons). Furthermore, before daily scrambler therapy sessions, adjustments of the electrode placement and dose, titrated to pain relief, are required. Finally, it has been observed that misapplication of the currents induces worse pain.

The proposed mechanism of scrambler therapy begins with the observation that chronic pain may represent dysregulation of the somatosensory nervous system.[52] The application of the electrical currents activates surface receptors (synthetic pain) and provides an opportunity for the patient to reinterpret signals as nonpain. The proposed mechanism depends on patients decoding pain information as nonpainful.

There are two relevant randomized trials of scrambler therapy. One study randomly assigned 52 patients with CIPN to receive either standard guideline–consistent therapy (opioids, gabapentinoids, tricyclic antidepressants) or scrambler therapy.[53] The primary outcome was the mean VAS pain score at 1 month. The mean scores before treatment were 8.1 in the control group and 8.0 in the scrambler group. The mean scores in both groups decreased, but the improvement was greater for scrambler therapy: from 5.8 to 0.7 (P < .0001). The scores were maintained at 2 and 3 months. The lack of an effective sham control is a significant limitation, as is the potential that the attention paid to the patient may have a salutary effect.

A subsequent trial randomly assigned 50 patients to either scrambler therapy or a conventional transcutaneous electrical nerve stimulation (TENS) therapy.[54] The primary endpoint of the study was the proportion of patients who experienced a reduction of more than 50% in either pain or tingling at 2 weeks, compared to baseline. Fifty-six percent of patients who received scrambler therapy achieved the goal, compared with 28% of those who received TENS therapy. There was a corresponding improvement in Global Impression of Change scores for neuropathy symptoms. Patients in the scrambler therapy arm were more likely to recommend the therapy to friends. The choice of TENS therapy as a control is confounded by the lack of data related to its efficacy in treating CIPN.

Approach to Acute Procedural Pain

Bone marrow biopsy and aspiration

Bone marrow biopsy and aspiration cause pain in 84% of patients, with intensity reported as severe in 8% to 35%.[55] Factors associated with greater pain are the following:[56]

  • Duration of the procedure (taking longer than 10 minutes).
  • Younger age.
  • Higher BMI.
  • Female sex.
  • Anxiety.
  • Site of examination (sternum being the most painful).
  • Inadequate information given before procedure.
  • Lack of physician experience.

Pharmacological interventions for pain control vary from local anesthesia,[57] to intravenous sedation with benzodiazepines and/or opioids,[58] to the use of inhaled nitrous oxide,[59] to premedication with opioids. Addressing anxiety is an important nonpharmacological intervention.[56]

Lumbar puncture

Lumbar puncture is a diagnostic and staging tool for hematologic malignancies and solid tumors involving the central nervous system. Patients can develop post–lumbar puncture headache. Headaches usually develop hours to days after the procedure and are caused by leakage of cerebrospinal fluid, possible compensatory intracranial vessel dilatation, or increased tension on brain and meninges.[60] The use of an atraumatic small-bore needle has been found to reduce to incidence of post–lumbar puncture headaches.[61,62] A Cochrane review that included 13 small randomized trials mostly in noncancer patients reported some evidence to support the use of caffeine, gabapentin, hydrocortisone, and theophylline to treat post–lumbar puncture headache, and a lack of efficacy for sumatriptan, adrenocorticotropic hormone, pregabalin, and cosyntropin.[63]

Treatment of Pain in Specific Patient Populations

Geriatric cancer patients

Geriatric patients are defined as persons aged 65 years or older, with a significant increase in incidence of comorbidity after age 75 years.[64,65] Up to 80% of geriatric cancer patients have pain over the course of their disease.[66] There are unique concerns in the treatment of cancer pain in this patient population, resulting from a narrowed therapeutic index of many analgesic and adjunctive medications. Age-related physiologic changes alter pharmacodynamics and pharmacokinetic drug properties (see Table 7).[67–70] Increased comorbidities and the resulting polypharmacy put patients at risk of drug-disease and drug-drug interactions. In addition, few clinical trials have been performed in patients older than 65 years to confirm drug safety and efficacy. For geriatric patients, analgesic medications need to be started at low doses and titrated up gradually. The rationales behind this approach include higher pain thresholds,[71] differences in pain expression,[72] and greater effects on physical and psychosocial function in this patient population.[73] For more information, see the Pain Assessment section.

Table 7. Pharmacokinetic and Pharmacodynamic Changesa
Age-Related Physiological Change Example of Affected Drugs
NSAID = nonsteroidal anti-inflammatory drug.
aAdapted from American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons,[67] Miller,[68] Bosilkovska et al.,[69] and Lexicomp Online.[70]
Decreased renal function Increased accumulation of morphine metabolites
Increased risk of NSAID-induced renal dysfunction
Increased body fat/decreased body water Delayed elimination of lipophilic drugs such as methadone
Cachexia Decreased fentanyl absorption from transdermal fentanyl patches [74]
Decreased hepatic function Results in increased oral bioavailability and half-life of opioids
– Decrease dose: hydromorphone, oxycodone
– Increase dose interval: morphine, oxycodone
Reduced protein binding Increased drug sensitivity/side effects
Reduced cytochrome P450 enzyme activity Increased drug concentrations of fentanyl and methadone
Decreased gastrointestinal motility Increased risk of opioid-induced constipation

Geriatric patients are also at risk of undertreatment because of underreported pain, difficulty communicating, and physician concerns about adverse effects and aberrant behavior. Persistent, inadequately controlled pain leads to poor outcomes in older patients, including the following:[67]

  • Functional impairment.
  • Slower rehabilitation.
  • Sleep and appetite changes.
  • Increased use of health care resources.

Treatment of an underlying depression can help facilitate pain treatment.[75]

The American Geriatrics Society (AGS) recommends the use of acetaminophen over nonsteroidal anti-inflammatory drugs (NSAIDs), when possible, for the treatment of mild to moderate musculoskeletal pain.[67] Compared with acetaminophen, NSAIDs carry an increased risk of gastrointestinal bleed/peptic ulcer disease, kidney dysfunction, and exacerbation of hypertension, and heart failure. The maximum recommended dose of acetaminophen is 3 g per day, or 2 g if patients have comorbidities predisposing them to hepatoxicity. When the use of NSAIDs is necessary, as in cases of chronic inflammatory pain, particular caution should be used in patients with reduced renal function, gastropathy, cardiovascular disease, or dehydration.

Strategies to prevent gastrointestinal adverse effects include the following:[67]

  • Co-administration of a gastroprotective agent such as an H2 receptor antagonist or a proton pump inhibitor.
  • Use of a COX-2–selective NSAID.
  • Use of a topical NSAID.

Opioids continue to be the mainstay of treating moderate to severe pain in geriatric patients. Older patients may be more sensitive to opioids because of the decreased renal and hepatic clearance of these drugs and their metabolites.[76,77] Geriatric patients may also need lower doses because they achieve greater analgesia from opioids. One retrospective study of opioid consumption in geriatric patients found that they need less opioid with acute and chronic pain therapy; they require less opioid regardless of route of administration; and incidental pain and/or neuropathic pain did not confound the correlation between age and opioid consumption but was associated with higher doses of opioids.[78] Geriatric patients are more susceptible to opioid adverse effects such as sedation and constipation. Guidelines recommend starting with lower opioid doses and increasing time between doses, with frequent reassessment of pain control to prevent underdosing. Meperidine should be avoided because of a lack of efficacy and increased risk of adverse effects, including seizure.[67]

Adjunct agents are often used with opioids to improve pain control for geriatric patients. Many of these adjunct agents are listed in the AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, to be avoided or used with caution in geriatric patients because of their increased risk of adverse effects [64] (see Table 8). For example, because of their high rate of anticholinergic effects, sedation, and risk of syncope and falls, tricyclic antidepressants commonly used to treat neuropathic pain conditions should be avoided in geriatric patients. Suggested alternatives for the treatment of neuropathic pain include duloxetine, gabapentin, topical capsaicin, and the lidocaine patch.[79]

Table 8. Potentially Inappropriate Medications Based on Beers Criteriaa
Drug/Class Example Rationale
CNS = central nervous system; COX-2 = cyclooxygenase-2; NSAIDs = nonsteroidal anti-inflammatory drugs.
aAdapted from American Geriatrics Society 2015 Beers Criteria Update Expert Panel.[64]
Tricyclic antidepressants Amitriptyline, clomipramine, imipramine Anticholinergic effects, sedation, orthostatic hypotension
Meperidine   Decreased efficacy, potential neurotoxicity
Non–COX-2–selective NSAIDs Ibuprofen, diclofenac, naproxen Gastrointestinal bleed risk, increased blood pressure, renal toxicity
Skeletal muscle relaxants Cyclobenzaprine, metaxalone, methocarbamol Anticholinergic effects, sedation, risk of fracture
CNS Avoid/reduce dose in renal impairment: CNS adverse effects
– Gabapentin
– Pregabalin
– Duloxetine
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  47. Hammack JE, Michalak JC, Loprinzi CL, et al.: Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 98 (1-2): 195-203, 2002. [PUBMED Abstract]
  48. Kautio AL, Haanpää M, Saarto T, et al.: Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage 35 (1): 31-9, 2008. [PUBMED Abstract]
  49. Kalso E, Tasmuth T, Neuvonen PJ: Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. Pain 64 (2): 293-302, 1996. [PUBMED Abstract]
  50. Barton DL, Wos EJ, Qin R, et al.: A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 19 (6): 833-41, 2011. [PUBMED Abstract]
  51. Hershman DL, Unger JM, Crew KD, et al.: Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L-Carnitine (SWOG S0715). J Natl Cancer Inst 110 (6): 669-676, 2018. [PUBMED Abstract]
  52. Marineo G: Inside the Scrambler Therapy, a Noninvasive Treatment of Chronic Neuropathic and Cancer Pain: From the Gate Control Theory to the Active Principle of Information. Integr Cancer Ther 18: 1534735419845143, 2019 Jan-Dec. [PUBMED Abstract]
  53. Marineo G, Iorno V, Gandini C, et al.: Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J Pain Symptom Manage 43 (1): 87-95, 2012. [PUBMED Abstract]
  54. Loprinzi C, Le-Rademacher JG, Majithia N, et al.: Scrambler therapy for chemotherapy neuropathy: a randomized phase II pilot trial. Support Care Cancer 28 (3): 1183-1197, 2020. [PUBMED Abstract]
  55. Vanhelleputte P, Nijs K, Delforge M, et al.: Pain during bone marrow aspiration: prevalence and prevention. J Pain Symptom Manage 26 (3): 860-6, 2003. [PUBMED Abstract]
  56. Hjortholm N, Jaddini E, Hałaburda K, et al.: Strategies of pain reduction during the bone marrow biopsy. Ann Hematol 92 (2): 145-9, 2013. [PUBMED Abstract]
  57. Kuivalainen AM, Niemi-Murola L, Widenius T, et al.: Comparison of articaine and lidocaine for infiltration anaesthesia in patients undergoing bone marrow aspiration and biopsy. Eur J Pain 14 (2): 160-3, 2010. [PUBMED Abstract]
  58. Mainwaring CJ, Wong C, Lush RJ, et al.: The role of midazolam-induced sedation in bone marrow aspiration/trephine biopsies. Clin Lab Haematol 18 (4): 285-8, 1996. [PUBMED Abstract]
  59. Steedman B, Watson J, Ali S, et al.: Inhaled nitrous oxide (Entonox) as a short acting sedative during bone marrow examination. Clin Lab Haematol 28 (5): 321-4, 2006. [PUBMED Abstract]
  60. Vilming ST, Kloster R: The time course of post-lumbar puncture headache. Cephalalgia 18 (2): 97-100, 1998. [PUBMED Abstract]
  61. Yu LM, Chen DX, Zhou QX, et al.: Effects of histamine on immunophenotype and notch signaling in human HL-60 leukemia cells. Exp Biol Med (Maywood) 231 (10): 1633-7, 2006. [PUBMED Abstract]
  62. Strupp M, Schueler O, Straube A, et al.: “Atraumatic” Sprotte needle reduces the incidence of post-lumbar puncture headaches. Neurology 57 (12): 2310-2, 2001. [PUBMED Abstract]
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Latest Updates to This Summary (02/12/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Pharmacological Therapies for Pain Control

Added text about a cross-sectional study, which showed that analgesic medications taken at longer dose intervals were associated with increased adherence, adjusting for pain, symptom, demographic, and setting variables in the model (cited Stapleton et al. as reference 16).

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of pain. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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The lead reviewers for Cancer Pain are:

  • Kristina B. Newport, MD, FAAHPM, HMDC (Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center)
  • Megan Reimann, PharmD, BCOP (Total CME)
  • Andrea Ruskin, MD (VA Connecticut Healthcare System)
  • Amy Wachholtz, PhD, MDiv, MS, ABPP (University of Colorado)

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PDQ® Supportive and Palliative Care Editorial Board. PDQ Cancer Pain. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /side-effects/pain/pain-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389387]

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Nausea and Vomiting Related to Cancer Treatment (PDQ®)–Health Professional Version


Nausea and Vomiting Related to Cancer Treatment (PDQ®)–Health Professional Version

Overview

Go to Patient Version

Prevention and control of nausea and vomiting (N&V) are paramount in the treatment of patients with cancer. Chemotherapy-induced N&V is one of the most common and distressing acute side effects of cancer treatment. It occurs in up to 80% of patients and can have a significant impact on a patient’s quality of life. N&V can also result in the following:

  • Serious metabolic derangements.
  • Nutritional depletion and anorexia.
  • Deterioration of the patient’s physical and mental status.
  • Esophageal tears.
  • Fractures.
  • Wound dehiscence.
  • Withdrawal from potentially useful and curative antineoplastic treatment.
  • Degeneration of self-care and functional ability.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Pathophysiology

Nausea is the subjective experience of an unpleasant, wavelike sensation in the back of the throat and/or the epigastrium that may culminate in vomiting (emesis). Vomiting (emesis) is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching involves the gastric and esophageal movements of vomiting without expulsion of vomitus; it is also referred to as dry heaves.

Progress has been made in understanding the neurophysiological mechanisms that control nausea and vomiting (N&V). Both are controlled or mediated by the central nervous system but by different mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from stimulation of a complex reflex that includes a convergence of afferent stimulation from the following:[1,2]

  • A chemoreceptor trigger zone (CTZ, area postrema).
  • The cerebral cortex and the limbic system in response to sensory stimulation (particularly smell and taste), psychological distress, and pain.
  • The vestibular-labyrinthine apparatus of the inner ear in response to body motion.
  • Peripheral stimuli from visceral organs and vasculature (via vagal and spinal sympathetic nerves) as a result of exogenous chemicals and endogenous substances that accumulate during inflammation, ischemia, and irritation.

Neurotransmitters (including serotonin, substance P, and dopamine) found in the CTZ, the vomiting center (thought to be located in the nucleus tractus solitarius), and enterochromaffin cells in the gastrointestinal tract release efferent impulses. These impulses are transmitted to the abdominal musculature, salivation center, and respiratory center. The relative contribution from these multiple pathways, culminating in N&V symptoms, is complex. It is postulated to account for agents’ variable emetogenicity (intrinsic emetogenicity and mitigating factors [i.e., dosage, administration route, and exposure duration]) and emetogenic profile (i.e., time to onset, symptom severity, and duration).[3,4]

References
  1. Wickham R: Evolving treatment paradigms for chemotherapy-induced nausea and vomiting. Cancer Control 19 (2 Suppl): 3-9, 2012. [PUBMED Abstract]
  2. Navari RM: Antiemetic control: toward a new standard of care for emetogenic chemotherapy. Expert Opin Pharmacother 10 (4): 629-44, 2009. [PUBMED Abstract]
  3. Cefalo MG, Ruggiero A, Maurizi P, et al.: Pharmacological management of chemotherapy-induced nausea and vomiting in children with cancer. J Chemother 21 (6): 605-10, 2009. [PUBMED Abstract]
  4. Darmani NA, Crim JL, Janoyan JJ, et al.: A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: evidence from the least shrew. Brain Res 1248: 40-58, 2009. [PUBMED Abstract]

General Risk Factors and Etiologies

Although most patients receiving chemotherapy are at risk of nausea and vomiting (N&V), the onset, severity, triggers, and duration vary. Factors related to the tumor, treatment, and patient all contribute to N&V, including tumor location, chemotherapy agents used, and radiation exposure.[1–3]

Patient-related factors may include the following:

  • Incidence and severity of N&V during past courses of chemotherapy. Patients with poor control of N&V during past chemotherapy cycles are likely to experience N&V in subsequent cycles.
  • History of chronic alcohol use. Patients with a history of chronic high intake of alcohol are less likely to experience cisplatin-induced N&V.[4]
  • Age. N&V is more likely to occur in patients younger than 50 years.[5]
  • Gender. N&V is more likely to occur in women.[5,6]
  • History of morning sickness or emesis during pregnancy.

Additional causal factors may include the following:

  • Fluid and electrolyte imbalances, such as hypercalcemia, volume depletion, or water intoxication.
  • Tumor invasion or growth in the gastrointestinal tract, liver, or central nervous system, especially the posterior fossa.
  • Constipation.
  • Certain drugs such as opioids.
  • Infection or septicemia.
  • Uremia.

Clinicians must be aware of all potential causes and factors of N&V, especially in cancer patients who may receive several treatments and medications. For more information about opioid-induced N&V, see the Adverse effects section in Cancer Pain.

Classifications

N&V have been classified as acute, delayed, anticipatory, breakthrough, refractory, and chronic, as outlined below:[7–9]

  • Acute N&V: N&V experienced during the first 24 hours after chemotherapy administration.[10]
  • Delayed (or late) N&V: N&V that occurs more than 24 hours after chemotherapy administration. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more consecutive days.
  • Anticipatory N&V (ANV): N&V that occurs before a new cycle of chemotherapy in response to conditioned stimuli such as the smells, sights, and sounds of the treatment room. ANV is a classically conditioned response that typically occurs after three or four chemotherapy treatments that led to acute or delayed N&V.
  • Breakthrough N&V: Vomiting that occurs within 5 days of prophylactic use of antiemetics and requires rescue.
  • Refractory N&V: N&V that does not respond to treatment.
  • Chronic N&V in patients with advanced cancer: N&V associated with a variety of potential etiologies. These etiologies are neither well known nor well researched, but potential causal factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic chemotherapy–induced, and radiation-induced mechanisms.[11]

The National Cancer Institute has published a descriptive terminology for adverse event reporting (see Table 1). A grading (severity) scale is provided for each term.

Table 1. National Cancer Institute’s Common Terminology Criteria for Adverse Events: N&Va
Adverse Event Grade Description
IV = intravenous; N&V = nausea and vomiting (emesis); TPN = total parenteral nutrition.
aAdapted from National Cancer Institute.[12]
bDefinition: A disorder characterized by a queasy sensation and/or the urge to vomit.
cDefinition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Nauseab 1 Loss of appetite without alteration in eating habits
2 Oral intake decreased without significant weight loss, dehydration, or malnutrition
3 Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated
4 Grade not assigned
5 Grade not assigned
Vomitingc 1 Intervention not indicated
2 Outpatient IV hydration; medical intervention indicated
3 Tube feeding, TPN, or hospitalization indicated
4 Life-threatening consequences; urgent intervention indicated
5 Death
References
  1. Farrell C, Brearley SG, Pilling M, et al.: The impact of chemotherapy-related nausea on patients’ nutritional status, psychological distress and quality of life. Support Care Cancer 21 (1): 59-66, 2013. [PUBMED Abstract]
  2. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PUBMED Abstract]
  3. Bouganim N, Dranitsaris G, Hopkins S, et al.: Prospective validation of risk prediction indexes for acute and delayed chemotherapy-induced nausea and vomiting. Curr Oncol 19 (6): e414-21, 2012. [PUBMED Abstract]
  4. Sullivan JR, Leyden MJ, Bell R: Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med 309 (13): 796, 1983. [PUBMED Abstract]
  5. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991. [PUBMED Abstract]
  6. Roila F, Tonato M, Basurto C, et al.: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 5 (1): 141-9, 1987. [PUBMED Abstract]
  7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PUBMED Abstract]
  8. Hesketh PJ: Chemotherapy-induced nausea and vomiting. N Engl J Med 358 (23): 2482-94, 2008. [PUBMED Abstract]
  9. Grunberg SM, Osoba D, Hesketh PJ, et al.: Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–an update. Support Care Cancer 13 (2): 80-4, 2005. [PUBMED Abstract]
  10. Wickham R: Nausea and vomiting. In: Yarbo CH, Frogge MH, Goodman M, eds.: Cancer Symptom Management. 2nd ed. Jones and Bartlett Publishers, 1999, pp 228-263.
  11. Schwartzberg L: Chemotherapy-induced nausea and vomiting: state of the art in 2006. J Support Oncol 4 (2 Suppl 1): 3-8, 2006. [PUBMED Abstract]
  12. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Bethesda, Md: U.S. Department of Health and Human Services, National Institutes of Health, 2017. Available online. Last accessed Feb. 14, 2024.

Anticipatory Nausea and Vomiting

Prevalence

The prevalence of anticipatory nausea and vomiting (ANV) has varied, owing to changing definitions and assessment methods.[1] Anticipatory nausea appears to occur in approximately 29% of patients receiving chemotherapy (about one of three patients), while anticipatory vomiting appears to occur in 11% of patients (about one of ten patients).[2] With the introduction of new pharmacological agents such as 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, it was anticipated that the prevalence of ANV might decline; however, studies have shown mixed results. One study found a lower incidence of ANV,[3] and three studies found comparable incidence rates.[2,4,5] It appears that the 5-HT3 agents reduce postchemotherapy vomiting but not postchemotherapy nausea,[2,5] and the resulting impact on ANV is unclear.

Classical Conditioning

Although other theoretical mechanisms have been proposed,[6] ANV appears to be best explained by classical conditioning, also known as Pavlovian or respondent conditioning.[7] In classical conditioning, a previously neutral stimulus (e.g., smells of the chemotherapy environment) elicits a conditioned response (e.g., ANV) after a number of pairings or learning trials. In cancer chemotherapy, the first few chemotherapy infusions are the learning trials. The chemotherapy drugs are the unconditioned stimuli that elicit postchemotherapy nausea and vomiting (N&V) in some patients. The drugs are paired with a variety of other neutral, environmental stimuli (e.g., smells of the setting, presence of the oncology nurse, chemotherapy room). These previously neutral stimuli then become conditioned stimuli and elicit ANV in future chemotherapy cycles. ANV is not an indication of psychopathology but is rather a learned response that, in other life situations (e.g., food poisoning), results in adaptive avoidance.

A variety of correlational studies provide empirical support for classical conditioning. For example, the prevalence of ANV before treatment with any chemotherapy is rare, and few patients ever experience ANV without previous postchemotherapy nausea.[8] Also, most studies have found (1) a higher probability of ANV with an increasing number of chemotherapy infusions, and (2) the intensity of ANV increasing as patients get closer to the time of their infusion.[9] In one experimental study, it was shown that a novel beverage could become a conditioned stimulus to nausea when paired with several chemotherapy treatments.[10]

Variables Correlated with ANV

Many variables have been investigated as potential risk factors that correlate with the incidence of ANV. There is no agreement on which factors predict ANV. However, a patient with fewer than three of the first eight characteristics listed below is unlikely to develop ANV. Screening after the first chemotherapy infusion could identify patients at increased risk.[11]

Variables Found to Correlate With ANV

  1. Age younger than 50 years.
  2. N&V after the last chemotherapy session.
  3. Posttreatment nausea described as moderate, severe, or intolerable.
  4. Posttreatment vomiting described as moderate, severe, or intolerable.
  5. Feeling warm or hot all over after the last chemotherapy session.
  6. Susceptibility to motion sickness.
  7. Female gender.
  8. High-state anxiety (anxiety reactive to specific situations).[12,13]
  9. Greater reactivity of the autonomic nervous system and slower reaction time.[14]
  10. Patient expectations of chemotherapy-related nausea before beginning treatment.[15,16]
  11. Percentage of chemotherapy infusions followed by nausea.[17]
  12. Postchemotherapy dizziness.
  13. Longer latency of onset of posttreatment N&V.[18]
  14. Emetogenic potential of various chemotherapeutic agents. Patients receiving drugs with a moderate to severe potential for posttreatment N&V are more likely to develop ANV.[12]
  15. History of morning sickness during pregnancy.

Treatment of ANV

Antiemetic drugs do not seem to control ANV once it has developed;[2] however, a variety of behavioral interventions has been investigated.[19] These interventions include the following:

  • Progressive muscle relaxation with guided imagery.[20]
  • Hypnosis.[21]
  • Systematic desensitization.[22]
  • Electromyography and thermal biofeedback.[23]
  • Distraction via the use of video games.[24,25]

Progressive muscle relaxation with guided imagery, hypnosis, and systematic desensitization has been studied the most and should be considered as treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients should be considered when ANV is identified. The earlier ANV is identified, the more likely treatment will be effective, so early screening and referral are essential. However, physicians and nurses underestimate the incidence of chemotherapy-induced N&V.[26][Level of evidence: II]

Clearly, the most important aspect of ANV is prevention of acute and delayed N&V associated with chemotherapy. Most antiemetics have not shown benefit for the treatment of ANV, but their use during chemotherapy may have a dramatic effect in decreasing the incidence of ANV. The only class of medication that has shown benefit in some studies is benzodiazepines, most commonly lorazepam.[27][Level of evidence: IV]

References
  1. Andrykowski MA: Defining anticipatory nausea and vomiting: differences among cancer chemotherapy patients who report pretreatment nausea. J Behav Med 11 (1): 59-69, 1988. [PUBMED Abstract]
  2. Morrow GR, Roscoe JA, Kirshner JJ, et al.: Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6 (3): 244-7, 1998. [PUBMED Abstract]
  3. Aapro MS, Kirchner V, Terrey JP: The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron. Br J Cancer 69 (5): 957-60, 1994. [PUBMED Abstract]
  4. Fernández-Marcos A, Martín M, Sanchez JJ, et al.: Acute and anticipatory emesis in breast cancer patients. Support Care Cancer 4 (5): 370-7, 1996. [PUBMED Abstract]
  5. Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000. [PUBMED Abstract]
  6. Reesal RT, Bajramovic H, Mai F: Anticipatory nausea and vomiting: a form of chemotherapy phobia? Can J Psychiatry 35 (1): 80-2, 1990. [PUBMED Abstract]
  7. Stockhorst U, Klosterhalfen S, Steingruber HJ: Conditioned nausea and further side-effects in cancer chemotherapy: a review. Journal of Psychophysiology 12 (suppl 1): 14-33, 1998.
  8. Morrow GR, Rosenthal SN: Models, mechanisms and management of anticipatory nausea and emesis. Oncology 53 (Suppl 1): 4-7, 1996. [PUBMED Abstract]
  9. Montgomery GH, Bovbjerg DH: The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 61 (5): 737-41, 1997. [PUBMED Abstract]
  10. Bovbjerg DH, Redd WH, Jacobsen PB, et al.: An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med 54 (6): 623-37, 1992 Nov-Dec. [PUBMED Abstract]
  11. Morrow GR, Roscoe JA, Hickok JT: Nausea and vomiting. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. Oxford University Press, 1998, pp 476-484.
  12. Andrykowski MA, Redd WH, Hatfield AK: Development of anticipatory nausea: a prospective analysis. J Consult Clin Psychol 53 (4): 447-54, 1985. [PUBMED Abstract]
  13. Roscoe JA, Morrow GR, Hickok JT, et al.: Biobehavioral factors in chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 2 (5): 501-8, 2004. [PUBMED Abstract]
  14. Kvale G, Psychol C, Hugdahl K: Cardiovascular conditioning and anticipatory nausea and vomiting in cancer patients. Behav Med 20 (2): 78-83, 1994 Summer. [PUBMED Abstract]
  15. Montgomery GH, Tomoyasu N, Bovbjerg DH, et al.: Patients’ pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea. Ann Behav Med 20 (2): 104-9, 1998 Spring. [PUBMED Abstract]
  16. Shelke AR, Roscoe JA, Morrow GR, et al.: Effect of a nausea expectancy manipulation on chemotherapy-induced nausea: a university of Rochester cancer center community clinical oncology program study. J Pain Symptom Manage 35 (4): 381-7, 2008. [PUBMED Abstract]
  17. Tomoyasu N, Bovbjerg DH, Jacobsen PB: Conditioned reactions to cancer chemotherapy: percent reinforcement predicts anticipatory nausea. Physiol Behav 59 (2): 273-6, 1996. [PUBMED Abstract]
  18. Chin SB, Kucuk O, Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. Am J Clin Oncol 15 (3): 262-7, 1992. [PUBMED Abstract]
  19. Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychol Bull 104 (3): 307-25, 1988. [PUBMED Abstract]
  20. Lyles JN, Burish TG, Krozely MG, et al.: Efficacy of relaxation training and guided imagery in reducing the aversiveness of cancer chemotherapy. J Consult Clin Psychol 50 (4): 509-24, 1982. [PUBMED Abstract]
  21. Redd WH, Andresen GV, Minagawa RY: Hypnotic control of anticipatory emesis in patients receiving cancer chemotherapy. J Consult Clin Psychol 50 (1): 14-9, 1982. [PUBMED Abstract]
  22. Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 307 (24): 1476-80, 1982. [PUBMED Abstract]
  23. Burish TG, Shartner CD, Lyles JN: Effectiveness of multiple muscle-site EMG biofeedback and relaxation training in reducing the aversiveness of cancer chemotherapy. Biofeedback Self Regul 6 (4): 523-35, 1981. [PUBMED Abstract]
  24. Kolko DJ, Rickard-Figueroa JL: Effects of video games on the adverse corollaries of chemotherapy in pediatric oncology patients: a single-case analysis. J Consult Clin Psychol 53 (2): 223-8, 1985. [PUBMED Abstract]
  25. Vasterling J, Jenkins RA, Tope DM, et al.: Cognitive distraction and relaxation training for the control of side effects due to cancer chemotherapy. J Behav Med 16 (1): 65-80, 1993. [PUBMED Abstract]
  26. Chan CW, Cheng KK, Lam LW, et al.: Psycho-educational intervention for chemotherapy-associated nausea and vomiting in paediatric oncology patients: a pilot study. Hong Kong Med J 14 (5 Suppl): 32-5, 2008. [PUBMED Abstract]
  27. Rock EM, Limebeer CL, Parker LA: Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. Exp Brain Res 232 (8): 2511-34, 2014. [PUBMED Abstract]

Etiology of Acute or Delayed Chemotherapy-Induced Nausea and Vomiting

Acute Nausea and Vomiting (N&V)

The incidence of acute N&V with moderate- or high-risk chemotherapy ranges from 30% to 90%.[1–3] It can result in significant morbidity and can negatively affect quality of life. However, in recent years many new antiemetic medications and combinations have become available, dramatically decreasing the incidence and severity of this dreaded complication. Risk factors include the following:

  • The emetogenic potential of the specific drug.
  • The dose used.
  • The treatment schedule.
  • How chemotherapy agents are combined.

For example, a drug with a low emetogenic potential given in high doses may cause a dramatic increase in the potential to induce N&V.[4] Standard doses of cytarabine rarely produce N&V, but high doses often do. Another influence is the use of drug combinations. Because most patients receive combination chemotherapy, the emetogenic potential of all of the drugs combined and individual drug doses needs to be considered.[5–9]

Other risk factors include the following:[10]

  • Poor control with previous chemotherapy.
  • Female gender.
  • Age younger than 50 years.
  • Experience with previous chemotherapy.
  • History of motion sickness.
  • History of morning sickness during pregnancy.
  • Dehydration.
  • Malnutrition.
  • Recent surgery.
  • Radiation therapy.

The American Society of Clinical Oncology (ASCO) provides a summary of intravenous chemotherapeutic agents and their respective risk of acute and delayed emesis.[10] For more information, see Table 2.

Table 2. Intravenous Chemotherapeutic Agents and Their Risk of Acute and Delayed Emesisa
High Risk Moderate Risk Low Risk Minimal Risk
aFrom Hesketh et al.[10]
Emesis has been documented in >90% of patients. Emesis has been documented in 30%–90% of patients. Emesis has been documented in 10%–30% of patients. Emesis has been documented in <10% of patients.
Anthracycline/cyclophosphamide combination Alemtuzumab Aflibercept Bevacizumab
Carmustine Azacitidine Atezolizumab Bleomycin
Cisplatin Bendamustine Belinostat Busulfan
Cyclophosphamide (≥1,500 mg/m2) Carboplatin Blinatumomab Cladribine
Dacarbazine Clofarabine Bortezomib Daratumumab
Dactinomycin Cyclophosphamide (<1,500 mg/m2) Brentuximab. Fludarabine
Mechlorethamine Cytarabine (>1,000 mg/m2) Cabazitaxel Nivolumab
Streptozotocin Daunorubicin Carfilzomib Obinutuzumab
  Doxorubicin Cetuximab Ofatumumab
  Epirubicin Cytarabine (<1,000 mg/m2) Pembrolizumab
  Idarubicin Docetaxel Pralatrexate
  Ifosfamide Elotuzumab Ramucirumab
  Irinotecan Eribulin Rituximab
  Irinotecan liposomal injection Etoposide Trastuzumab
  Oxaliplatin Fluorouracil Vinblastine
  Romidepsin Gemcitabine Vincristine
  Temozolomide Ipilimumab Vinorelbine
  Thiotepa Ixabepilone  
  Trabectedin Methotrexate  
    Mitomycin  
    Mitoxantrone  
    Nab-paclitaxel  
    Necitumumab  
    Paclitaxel  
    Panitumumab  
    Pegylated liposomal doxorubicin  
    Pemetrexed  
    Pertuzumab  
    Temsirolimus  
    Topotecan  
    Trastuzumab-emtansine  

ASCO also provides a summary of oral chemotherapeutic agents and their respective risk of acute and delayed emesis.[10] For more information, see Table 3.

Table 3. Oral Chemotherapeutic Agents and Their Risk of Acute and Delayed Emesisa
High Risk Moderate Risk Low Risk Minimal Risk
aFrom Hesketh et al.[10]
Emesis has been documented in >90% of patients. Emesis has been documented in 30%–90% of patients. Emesis has been documented in 10%–30% of patients. Emesis has been documented in <10% of patients.
Altretamine Bosutinib Afatinib Chlorambucil
Procarbazine Cabozantinib Alectinib Erlotinib
  Ceritinib Axitinib Gefitinib
  Crizotinib Capecitabine Hydroxyurea
  Cyclophosphamide Cobimetinib Melphalan
  Imatinib Dabrafenib Methotrexate
  Lenvatinib Dasatinib Pomalidomide
  Temozolomide Etoposide Ruxolitinib
  Trifluridine-tipiracil Everolimus Sorafenib
  Vinorelbine Fludarabine Thioguanine
    Ibrutinib Vemurafenib
    Idelalisib Vismodegib
    Ixazomib  
    Lapatinib  
    Lenalidomide  
    Olaparib  
    Osimertinib  
    Nilotinib  
    Palbociclib  
    Panobinostat  
    Pazopanib  
    Ponatinib  
    Regorafenib  
    Sonidegib  
    Sunitinib  
    Thalidomide  
    Trametinib  
    Vandetanib  
    Venetoclax  
    Vorinostat  

Delayed N&V

Delayed (or late) N&V occurs more than 24 hours after chemotherapy administration. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or given on 2 or more consecutive days.[1,11,12]

  • Etiologies: Patients who experience acute emesis with chemotherapy are significantly more likely to have delayed emesis.
  • Risk factors: All predictive characteristics for acute emesis are considered risk factors for delayed emesis.
  • Emetic classifications: For more information, see the Acute Nausea and Vomiting (N&V) section.
References
  1. Hesketh PJ, Sanz-Altamira P, Bushey J, et al.: Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 20 (5): 1043-7, 2012. [PUBMED Abstract]
  2. Schwartzberg L: Addressing the value of novel therapies in chemotherapy-induced nausea and vomiting. Expert Rev Pharmacoecon Outcomes Res 14 (6): 825-34, 2014. [PUBMED Abstract]
  3. Sekine I, Segawa Y, Kubota K, et al.: Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci 104 (6): 711-7, 2013. [PUBMED Abstract]
  4. Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000. [PUBMED Abstract]
  5. Viale PH, Grande C, Moore S: Efficacy and cost: avoiding undertreatment of chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs 16 (4): E133-41, 2012. [PUBMED Abstract]
  6. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PUBMED Abstract]
  7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PUBMED Abstract]
  8. Phillips RS, Gopaul S, Gibson F, et al.: Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database Syst Rev (9): CD007786, 2010. [PUBMED Abstract]
  9. Olver I, Clark-Snow RA, Ballatori E, et al.: Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential. Support Care Cancer 19 (Suppl 1): S33-6, 2011. [PUBMED Abstract]
  10. Hesketh PJ, Kris MG, Basch E, et al.: Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 35 (28): 3240-3261, 2017. [PUBMED Abstract]
  11. Geling O, Eichler HG: Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 23 (6): 1289-94, 2005. [PUBMED Abstract]
  12. Fleishman SB, Mahajan D, Rosenwald V, et al.: Prevalence of Delayed Nausea and/or Vomiting in Patients Treated With Oxaliplatin-Based Regimens for Colorectal Cancer. J Oncol Pract 8 (3): 136-40, 2012. [PUBMED Abstract]

Prevention and Management of Acute or Delayed Nausea and Vomiting

Several organizations—including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Pediatric Oncology Group of Ontario—have published antiemetic guidelines for their members. PDQ does not endorse specific guidelines, but examples can be found in the literature.[1–4]

Antiemetic agents are the most common intervention for treatment-related nausea and vomiting (N&V). The basis for antiemetic therapy is the neurochemical control of vomiting. Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and numerous other endogenous neurotransmitters.[5,6] Many antiemetics act by competitively blocking receptors for these substances, which inhibit stimulation of peripheral nerves at the CTZ and possibly at the vomiting center.

Current guidelines [2,7] recommend that prechemotherapy management of chemotherapy-induced N&V (CINV) be based on the emetogenic potential of the chemotherapy agent(s) selected. For patients receiving regimens with high emetogenic potential, the combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, neurokinin-1 (NK-1) receptor antagonist, and dexamethasone with or without olanzapine is recommended prechemotherapy. Aprepitant (if chosen as the NK-1 receptor antagonist prechemotherapy), olanzapine, and dexamethasone are recommended for the prevention of delayed emesis. Guidelines differ with respect to using a three- or four-drug regimen for prophylaxis for highly emetogenic chemotherapy. One guideline includes the option of omitting an NK-1 antagonist completely if dexamethasone, palonosetron, and olanzapine are used.[7]

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone is used prechemotherapy. Patients receiving carboplatin (area under the curve ≥4 mg/mL) may also receive an NK-1 receptor antagonist. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.

For regimens with low emetogenic potential, dexamethasone or a 5-HT3 receptor antagonist is recommended. For regimens with minimal emetogenic risk, no prophylaxis is recommended.[2,7]

Antiemetic guidelines [2,7] have included oral 5-HT3 receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low.[8]

Studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[8–10] One study suggested that patients who are highly expectant of nausea appear to experience more postchemotherapy nausea.[11] In addition, the current and new agents that have been used as prophylaxis for acute and delayed CINV have not been studied for use in established CINV. One study reported the effective use of intravenous (IV) palonosetron and dexamethasone to prevent CINV in patients receiving multiple-day chemotherapy.[12]

Table 4 summarizes prechemotherapy and postchemotherapy recommendations by emetogenic potential.

Table 4. Antiemetic Recommendations by Emetic Risk Categoriesa,b
Emetic Risk Category ASCO Guidelines MASCC Guidelines NCCN Guidelines
5-HT3 = 5-hydroxytryptamine-3; ASCO = American Society of Clinical Oncology; AUC = area under the curve; MASCC = Multinational Association of Supportive Care in Cancer; NCCN = National Comprehensive Cancer Network; NK-1 = neurokinin-1.
aAdapted from National Comprehensive Cancer Network,[7] Roila et al.,[13] and Hesketh et al.[2]
bOrder of listed antiemetics does not reflect preference.
High risk (>90%) 4-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine recommended prechemotherapy 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone prechemotherapy
Note: Depending on NK-1 antagonist, dosing may be ≥1 day
Olanzapine and dexamethasone to be continued on days 2–4 OR: Olanzapine (5–10 mg), palonosetron (0.25 mg), and dexamethasone (12 mg) prechemotherapy, followed by olanzapine (5–10 mg) daily on days 2–4
For anthracycline and cyclophosphamide combinations only, olanzapine to be continued on days 2–4 OR: Four-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine recommended prechemotherapy
Note: Depending on NK-1 antagonist, dosing may be ≥1 day Olanzapine and dexamethasone to be continued on days 2–4
Note: Depending on NK-1 antagonist, dosing may be ≥1 day
Moderate risk (30%–90%) Carboplatin AUC ≥4 mg/mL per min; 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy For carboplatin-containing regimens, 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy 2-drug combination of 5-HT3 receptor antagonist and dexamethasone followed by dexamethasone (8 mg ) on days 2–3 OR: 5-HT3 receptor antagonist monotherapy on days 2–3
For patients receiving chemotherapies of moderate emetic risk excluding carboplatin AUC ≥4 mg/mL per min, 2-drug combination of 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy For patients receiving chemotherapies of moderate emetic risk excluding carboplatin, 2-drug combination of 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy OR: Olanzapine (5–10 mg), palonosetron (0.25 mg), and dexamethasone (12 mg) prechemotherapy, followed by olanzapine (5–10 mg daily) on days 2–3
For patients receiving cyclophosphamide, doxorubicin, oxaliplatin, and other moderate-emetic-risk antineoplastic agents known to cause delayed nausea, dexamethasone may be offered on days 2–3 for prevention of delayed emesis For patients receiving cyclophosphamide, doxorubicin, or oxaliplatin, dexamethasone may be offered on days 2–3 for prevention of delayed emesis OR: 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy, followed by dexamethasone (8 mg ) on days 2–3
Note: depending on NK-1 antagonist, dosing may be ≥1 day
Low risk (10%–30%) Single dose of 5-HT3 receptor antagonist or dexamethasone (8 mg) recommended Single dose of 5-HT3 receptor antagonist or dexamethasone or dopamine antagonist recommended Single dose of 5-HT3 receptor antagonist or dexamethasone (8–12 mg) or metoclopramide (10–20 mg) or prochlorperazine (10 mg) recommended
Minimal risk (<10%) No antiemetic administered routinely pre- or postchemotherapy No routine prophylaxis recommended No routine prophylaxis recommended

Most drugs with proven antiemetic activity can be categorized into one of the following groups:

  • Competitive antagonists at dopaminergic (D2 subtype) receptors:
    • Phenothiazines.
    • Butyrophenones (droperidol, haloperidol).
    • Substituted benzamides (metoclopramide).
  • Competitive antagonists at serotonergic (5-hydroxytryptamine-3 or 5-HT3 subtype) receptors.
  • Substance P antagonists (NK-1 receptor antagonists).
  • Corticosteroids.
  • Benzodiazepines (lorazepam).
  • Cannabinoids.

Although Table 5 lists all routes of administration, the intramuscular (IM) route is used only when no other access is available. IM delivery is painful, is associated with erratic absorption of drug, and may lead to sterile abscess formation or fibrosis of the tissues. This is particularly important when more than one or two doses of a drug are to be given.

Table 5. Prevention of Acute or Delayed CINV
Drug Category Medication Dose Available Route Comment(s) Reference(s)
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; CINV = chemotherapy-induced nausea and vomiting; EPS = extrapyramidal symptoms; IM = intramuscular; IV = intravenous; NK-1 = neurokinin-1; PO = oral; PR = rectal; qd = every day; SL = sublingual; SQ = subcutaneous.
aDolasetron may be difficult to obtain from the manufacturer.
Dopamine antagonists: phenothiazines Chlorpromazine 10–25 mg PO q4–6h PO, IM Prolongs QT interval [14,15][Level of evidence: II]
25–50 mg IM q3–4h
Prochlorperazine 25 mg PR q12h PO, IM, IV, PR Less sedation but increased risk of EPS [14]
5–10 mg PO/IM/IV q6–8h
Promethazine 12.5–25 mg q4–6h PO, IM, IV, PR Vesicant [14][Level of evidence: IV]
Weak antiemetic
Dopamine antagonists: butyrophenones Haloperidol 0.5–5 mg q24h in divided doses PO, IV, IM Used for treatment [16][Level of evidence: III]
Rarely used for prophylaxis
Prolongs QT interval
Droperidol 1–2.5 mg/dose q2–6h IV, IM Prolongs QT interval [14,16][Level of evidence: III]
Used primarily for treatment
Dopamine antagonists: substituted benzamides Metoclopramide Prevention of CINV: 1–2 mg/kg IV x1 dose prechemotherapy; then x2 doses q2h; then x3 doses q3h PO, IM, IV EPS associated with higher doses; patients <30 y [14]
Pretreat with diphenhydramine to prevent EPS
Treatment of CINV: 10–40 mg PO q4–6h; up to 0.5 mg/kg PO q6h Enhances gastric emptying
Trimethobenzamide 300 mg PO q6–8h PO, IM Unavailable in United States [14,17][Level of evidence: II]
200 mg IM q6–8h
Serotonin (5-HT3) receptor antagonists Dolasetrona 100 mg within 1 h prechemotherapy PO IV form withdrawn from market due to QTc prolongation [14]
Granisetron 1–2 mg PO or 10 µg/kg up to 1 mg IV within 1 h of chemotherapy IV, PO, topical, SQ Transdermal patch applied 24 h prechemotherapy; may be left in place ≤1 wk [14]
3.1 mg/24 h transdermally
10 mg SQ ≥30 min prechemotherapy SQ extended release should not be given more than once q7d
Ondansetron 0.15 mg/kg IV 30 min prechemotherapy; then may be repeated 4 and 8 h later; maximum: 16 mg/24 h PO, IV Doses >16 mg not recommended due to QTc prolongation [14,16][Level of evidence: I]
24 mg PO 30 min before highly emetogenic single-day chemotherapy
8 mg PO 30 min before moderate-emetogenic-risk chemotherapy, followed in 8 h by 8 mg then 8 mg PO q12h for 1–2 d Post-approval studies show 8 mg IV equivalent to larger doses
Palonosetron 0.25 mg IV or 0.5 mg PO 30 min prechemotherapy day 1 IV, PO   [14]
Substance P antagonists (NK-1 receptor antagonists) Aprepitant 125 mg prechemotherapy day 1, then 80 mg daily x2 d PO CYP3A4 enzyme inhibitor [14]
CYP2C9 enzyme inducer
Aprepitant, emulsion 130 mg prechemotherapy day 1 IV Dose equivalent to fosaprepitant 150 mg [14]
CYP3A4 enzyme inhibitor
CYP2C9 enzyme inducer
Fosaprepitant 150 mg prechemotherapy day 1 IV CYP3A4 enzyme inhibitor [14]
CYP2C9 enzyme inducer
Netupitant (combined with palonosetron) Netupitant 300 mg/palonosetron 0.5 mg prechemotherapy day 1 PO CYP3A4 enzyme inhibitor [14]
Fosnetupitant (combined with palonosetron) Fosnetupitant 235 mg/palonosetron 0.25 mg prechemotherapy day 1 IV CYP3A4 enzyme inhibitor [14,18]
Rolapitant 180 mg prechemotherapy day 1 PO/IV Anaphylactic reactions have occurred with IV infusion [14]
Doses must be separated by ≥14 d
CYP2D6 enzyme inhibitor
Corticosteroids Dexamethasone 12–20 mg before high-emetic-risk chemotherapy, followed by 8 mg 1–2 times/d for 3 d PO, IV Combined with a 5-HT3 receptor antagonist [14]
8 mg before moderate-emetic-risk chemotherapy, followed by 8 mg/d for 2 d When given with (fos)aprepitant or (fos)netupitant, 12 mg = 20 mg on day 1, and 8 mg is equivalent on subsequent days due to drug interaction
Methylprednisolone 0.5–1 mg/kg 30 min pre- and 4 and 8 h postchemotherapy PO, IV Maximum 4 mg/kg/d; may also be given as single dose prechemotherapy [16][Level of evidence: III]
Benzodiazepines Alprazolam 0.25–1 mg q6–8h PO Shortest half-life in drug class [14,19][Level of evidence: I]
Lorazepam 0.5–2 mg q6h PO, SL, IM, IV Most-commonly used in drug class [14]
Atypical antipsychotics Olanzapine Prevention of acute and delayed CINV in combination with 5-HT3 receptor antagonist, dexamethasone, and NK-1 antagonist: 10 mg PO qd days 1–4 PO Consider giving at bedtime due to sedation [20][Level of evidence: I]
Treatment of breakthrough CINV: 10 mg PO daily x3 d [21][Level of evidence: I]
Other pharmacologic agents Dronabinol 5 mg/m2 PO 1–3 h prechemotherapy, followed every 2–4 h by same dose, up to 4–6 doses/d PO   [14]
Dose may be increased in increments of 2.5 mg/m2, up to maximum 15 mg/m2
Nabilone 1–2 mg bid, maximum 6 mg/d in 3 doses PO May be continued up to 48 h postchemotherapy [14]
Cannabis No current data on dosing Inhaled, PO Currently, not enough data to recommend Cannabis products for prevention/treatment of CINV [22][Level of evidence: IV]
Ginger 0.5–2 g/d prechemotherapy PO Current literature demonstrates conflicting efficacy results [23,24][Level of evidence: II]

Competitive Dopamine (D2) Antagonists

Phenothiazines

Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally.

In selecting phenothiazines, the primary consideration is assessing differences in adverse effect profiles, which correlate with the structural classes of the drugs. Generally, aliphatic phenothiazines (e.g., chlorpromazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine) are associated with less sedation but higher incidence of extrapyramidal symptoms (EPS) such as acute dystonias, akathisia, neuroleptic malignant syndrome (uncommon), and, rarely, akinesias and dyskinesias. Marked hypotension may also result if IV doses are administered rapidly at high doses. The concomitant use of H1 blockers, such as diphenhydramine, can often decrease the risk and severity of EPS. Phenothiazines may be of particular value in treating patients who experience delayed N&V with cisplatin regimens.[25–29][Level of evidence: I] Given their anticholinergic properties, phenothiazines are listed in the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.[30]

Butyrophenones

Droperidol and haloperidol represent butyrophenones, another class of dopaminergic (D2 subtype) receptor antagonists that are structurally and pharmacologically similar to the phenothiazines. While droperidol is used primarily as an adjunct to anesthesia induction, haloperidol is indicated as a neuroleptic antipsychotic drug; however, both agents have some antiemetic activity. Results of small, uncontrolled, open-label studies show some efficacy for haloperidol in patients undergoing palliative care.[31,32] Both agents may produce EPS, akathisia, hypotension, and sedation.

Substituted benzamides

Metoclopramide is a substituted benzamide, which, before serotonin (5-HT3) receptor antagonists were introduced, was considered the most effective antiemetic agent against highly emetogenic chemotherapy. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses, probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT3 receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. Metoclopramide has also been safely given by IV bolus injection at higher single doses (up to 6 mg/kg) and by continuous IV infusion, with or without a loading bolus dose, with efficacy comparable to that of multiple intermittent dosing schedules.[33–35]

Metoclopramide is associated with akathisia and dystonic EPS. Akathisia is seen more frequently in patients older than 30 years, and dystonic EPS are seen more commonly in patients younger than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPS.[36] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia is best treated by lowering the metoclopramide dose, changing to a different agent, or adding a benzodiazepine.

Trimethobenzamide is believed to act centrally on the CTZ by blocking emetic impulses. It has been studied in a limited number of oncology patients experiencing nausea from various chemotherapy regimens. Compared with placebo, trimethobenzamide, 200 mg IM every 6 hours for 2 days, significantly reduced episodes of N&V.[17]

5-HT3 Receptor Antagonists

Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Agents in this class are thought to prevent N&V by preventing serotonin, which is released from enterochromaffin cells in the gastrointestinal (GI) mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves.[37–39] The 5-HT3 receptor antagonists may also block serotonin stimulation at the CTZ and other CNS structures. Major side effects of this class of medications include mild headache and constipation. Multiple studies have shown that the 5-HT3 receptor antagonists are most effective when given in conjunction with steroids.

Comparison of agents

Studies suggest that there are no major differences in efficacy or toxicity of the three first-generation 5-HT3 receptor antagonists (dolasetron, granisetron, and ondansetron) in the treatment of acute CINV. These three agents are equivalent in efficacy and toxicity when used in appropriate doses.[40,41]; [42][Level of evidence: I] These agents have been shown to be effective in the first 24 hours postchemotherapy (acute phase), but not on days 2 to 5 postchemotherapy (delayed phase).

Palonosetron, the second-generation 5-HT3 receptor antagonist, has been approved for the control of acute emesis with highly and moderately emetogenic chemotherapy and approved for delayed emesis in patients receiving moderately emetogenic chemotherapy.[43]; [44][Level of evidence: I]

Despite the use of both first- and second-generation 5-HT3 receptor antagonists, the control of acute CINV, especially delayed N&V, is suboptimal. There is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[8,45–47]

Ondansetron

Several studies have demonstrated that ondansetron produces an antiemetic response that is equal or superior to that of high doses of metoclopramide, but with an improved toxicity profile, compared with that of dopaminergic antagonist agents.[48–51][Level of evidence: I]; [52,53] A randomized trial of ondansetron, 8 mg and 32 mg, given prophylactically to patients receiving cisplatin found no difference between the doses.[54] A single-center, retrospective chart review has reported ondansetron-loading doses of 16 mg/m2 IV (maximum, 24 mg) to be safe in infants, children, and adolescents.[55] However, data reported to the U.S. Food and Drug Administration (FDA) raise concerns about QT prolongation and potentially fatal arrhythmias with a single 32-mg IV dose. Current drug labeling calls for a maximum single 16-mg IV dose.[56]

Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years, including elderly patients and patients with renal insufficiency. Oral ondansetron is given 3 times daily starting 30 minutes before chemotherapy and continuing for up to 2 days after chemotherapy is completed. Ondansetron clearance is diminished in patients with severe hepatic insufficiency; these patients receive a single injectable or oral dose no higher than 8 mg. There is currently no information evaluating the safety of repeated daily ondansetron doses in patients with hepatic insufficiency. Other effective dosing schedules, such as a continuous IV infusion (e.g., 1 mg/h for 24 h) or oral administration, have also been evaluated.[57]

The major adverse effects of ondansetron include the following:[58]

  • Headache (which can be treated with mild analgesics).
  • Constipation.
  • Fatigue.
  • Dry mouth.
  • Transient asymptomatic elevations in liver function tests (alanine and aspartate transaminases), which may be related to concurrent cisplatin administration.

Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events.[59] Rare electrocardiogram changes in the form of QTc prolongation may occur. In addition, a few case reports have implicated ondansetron in causing EPS. However, it is not clear whether the events described were in fact EPS. In other reports, the evidence is confounded by concurrent use of other agents that are known to produce EPS. Nevertheless, the greatest advantage of serotonin receptor antagonists over dopaminergic receptor antagonists is that they have fewer adverse effects. Despite prophylaxis with ondansetron, many patients receiving doxorubicin, cisplatin, or carboplatin will experience acute and delayed N&V.[60] Randomized, double-blind, placebo-controlled trials support the addition of aprepitant, an NK-1 receptor antagonist, for additional mitigation of N&V.[61,62][Level of evidence: I]

Granisetron

Granisetron has shown efficacy in preventing and controlling N&V at a broad range of doses. In the United States, granisetron injection, extended-release injection, transdermal patch, and oral tablets are approved for initial and repeat prophylaxis for patients receiving emetogenic chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically and pharmacokinetically distinct from ondansetron; however, clinically it is equally efficacious and equally safe.[60–63][Level of evidence: I]

The subcutaneous extended-release formulation of granisetron was compared with palonosetron in the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy in a randomized, double-blind noninferiority phase III trial.[64] Patients were randomly assigned to receive IV palonosetron, 0.25 mg; or subcutaneous granisetron, 5 mg or 10 mg. Patients who received palonosetron in cycle 1 were then randomly assigned to receive granisetron in cycles 2 through 4. Both subcutaneous doses of granisetron were noninferior to palonosetron in cycle 1 of moderately emetogenic chemotherapy (74.8% and 76.9% for granisetron 5 mg and 10 mg, respectively, vs. 75.0% for palonosetron) and highly emetogenic chemotherapy (77.7% and 81.3% for granisetron 5 mg and 10 mg, respectively, vs. 80.7% for palonosetron). Subcutaneous granisetron was not superior to palonosetron in the prevention of delayed CINV after highly emetogenic chemotherapy.

Currently, granisetron is approved for use without dosage modification in patients older than 2 years, including elderly patients and patients with hepatic and renal insufficiency.

Dolasetron

Oral formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses. However, the drug may be difficult to obtain from the manufacturer. Oral dolasetron may be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron was given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy; however, injection formulations are no longer approved for CINV because of the risk of QTc interval prolongation.[65]

The effectiveness of oral dolasetron in the prevention of CINV has been proven in a large randomized, double-blind, comparative trial of 399 patients.[66][Level of evidence: I] Oral dolasetron was administered in the range of 25 to 200 mg 1 hour before chemotherapy. The other study arm consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy and every 8 hours after chemotherapy for a total of three doses. Rates of complete response (CR), defined as no emetic episodes and no use of escape antiemetic medications, improved with increasing doses of dolasetron. Both dolasetron 200 mg and ondansetron had significantly higher CR rates than did dolasetron 25 or 50 mg.

Palonosetron

Palonosetron is a 5-HT3 receptor antagonist (second generation) that has antiemetic activity at both central and GI sites. Palonosetron is FDA approved for the prevention of acute N&V associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy and for the prevention of delayed N&V associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Compared with the older 5-HT3 receptor antagonists, palonosetron has a higher binding affinity to the 5-HT3 receptors, a higher potency, a significantly longer half-life (approximately 40 hours, four to five times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile.[67][Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[68–72]

In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and delayed periods for patients who received 0.25 mg of palonosetron alone, compared with either ondansetron or dolasetron alone.[43]; [44][Level of evidence: I] Dexamethasone was not given with the 5-HT3 receptor antagonists in these studies, and it is not yet known whether the differences in CR would persist if it were used.

In another study,[73][Level of evidence: I] 650 patients receiving highly emetogenic chemotherapy (cisplatin ≥60 mg/m2) also received either dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg). Single-dose palonosetron was as effective as ondansetron in preventing acute CINV with dexamethasone pretreatment. It was significantly more effective than ondansetron throughout the 5-day postchemotherapy period. In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, one author [74] reported that the CR rates for both acute and delayed CINV were maintained with single IV doses of palonosetron without concomitant corticosteroids.

NK-1 Receptor Antagonists (Substance P Antagonists)

Substance P, found in the vagal afferent neurons in the nucleus tractus solitarius, the abdominal vagus, and the area postrema, induces vomiting. NK-1 receptor antagonists, including aprepitant, fosaprepitant, netupitant, fosnetupitant, and rolapitant, block substance P from binding to the NK-1 receptor. In combination with a 5-HT3 receptor antagonist and a corticosteroid, NK-1 receptor antagonists are indicated for the prevention of acute and delayed N&V associated with initial and repeat courses of high and moderately emetogenic chemotherapy. There have been no randomized trials comparing the individual NK-1 receptor antagonists. All are considered effective at their FDA-approved doses.

Aprepitant and fosaprepitant

Clinical trials [75–78] demonstrated that the addition of aprepitant to a 5-HT3 receptor antagonist plus dexamethasone before cisplatin chemotherapy improved the control of acute emesis, compared with a 5-HT3 receptor antagonist plus dexamethasone. This regimen also improved the control of delayed emesis, compared with placebo. In two randomized, double-blind, parallel, controlled studies, patients received cisplatin (≥70 mg/m2) and were randomly assigned to receive either (1) standard therapy with ondansetron and dexamethasone prechemotherapy and dexamethasone on days 2 to 4 postchemotherapy or (2) standard therapy plus aprepitant prechemotherapy on days 2 and 3.[79,80][Level of evidence: I] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute and the delayed periods. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[81][Level of evidence: I] Finally, aprepitant has been shown to be efficacious in preventing N&V in breast cancer patients receiving highly emetogenic chemotherapy with cyclophosphamide and doxorubicin.[82]

The benefit of aprepitant has also been demonstrated outside of highly emetogenic chemotherapy. The addition of aprepitant to ondansetron and dexamethasone before moderately emetogenic chemotherapy versus ondansetron and dexamethasone alone resulted in improved CINV outcomes.[83–85] An alternative dosing strategy was evaluated in a randomized, double-blind, placebo-controlled, phase III crossover study in patients receiving 5-day cisplatin combination chemotherapy for germ cell tumors.[86] In addition to standard antiemetic therapy, patients received aprepitant 125 mg on day 3, followed by aprepitant 80 mg on days 4 through 7. There was a significant improvement in CINV CR with the three-drug regimen.

Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration.[87] Fosaprepitant is approved as a single dose of 150 mg before chemotherapy on day 1, as an alternative to the 3-day oral aprepitant regimen. As demonstrated in a randomized, double-blind study of patients receiving cisplatin chemotherapy, single-dose IV fosaprepitant (150 mg) given with ondansetron and dexamethasone was noninferior to the standard 3-day dosing of oral aprepitant in preventing CINV.[87] Fosaprepitant is formulated with polysorbate 80, a solubilizing agent, which can cause rare but serious hypersensitivity reactions.[88,89] Aprepitant is also available in a parenteral emulsion form, which has a reduced risk of thrombophlebitis and hypersensitivity reactions.[90]

Netupitant and fosnetupitant

Netupitant is a competitive antagonist to the NK-1 receptor that is marketed as either an oral fixed-combination product containing 300 mg of netupitant and 0.5 mg of palonosetron (NEPA) or an IV fixed-combination product containing 235 mg of fosnetupitant and 0.25 mg of palonosetron. Of note, the IV formulation of NEPA does not contain the surfactant polysorbate 80 or any other allergenic excipients and could be considered for patients who have had hypersensitivity reactions to fosaprepitant.[91][Level of evidence: I] It is given with dexamethasone before chemotherapy to prevent both acute and delayed CINV. This drug combination has been used successfully for prevention of CINV in a single cycle of both highly and moderately emetogenic chemotherapy regimens.[92,93]

The antiemetic benefit of NEPA was demonstrated throughout multiple cycles of chemotherapy in a randomized, double-blind, controlled trial.[94][Level of evidence: I] Patients starting combination anthracycline/cyclophosphamide regimens were randomly assigned to receive oral fixed-dose NEPA with 12 mg of dexamethasone or 0.5 mg of oral palonosetron with 20 mg of dexamethasone. The percentage of patients with a CR was significantly greater for NEPA than for oral palonosetron for cycles 1 to 4. The most common treatment-related side effects were headache and constipation, which were similar between the two arms.

A Japanese study compared single-agent fosnetupitant to fosaprepitant combined with palonosetron and dexamethasone in patients receiving highly emetic chemotherapy.[95][Level of evidence: I] Fosnetupitant was found to be noninferior to the fosaprepitant regimen. Additionally, fosnetupitant had an improved safety profile with fewer injection site reactions (11% vs. 20.6%, P < .001). Single-agent fosnetupitant is not currently FDA approved in the United States.

Similarly, NEPA has been compared with granisetron and aprepitant in patients receiving highly emetogenic chemotherapy. In a phase III, randomized, double-blind study, a single dose of NEPA was shown to be noninferior to a 3-day regimen of granisetron and aprepitant. Additionally, significantly more patients did not need rescue medications when they received NEPA (96.6%), compared with those who received granisetron plus aprepitant (93.5%). Toxicities were similar between treatment arms.[96][Level of evidence: I]

Rolapitant

Rolapitant is an oral competitive NK-1 receptor inhibitor. It is approved for the prevention of delayed N&V associated with highly and moderately emetogenic chemotherapy. In addition to granisetron and dexamethasone, rolapitant significantly increases CINV CR versus standard therapy plus placebo for patients receiving both highly and moderately emetogenic chemotherapy. Unlike other drugs in its class, rolapitant has no effect on cytochrome P450 3A4 enzymes; therefore, no dose adjustment for dexamethasone is required.[97–99] The IV formulation has been associated with hypersensitivity reactions, including anaphylaxis, which have limited its use.[100]

Corticosteroids

Steroids are commonly used in combination with other antiemetics. Their antiemetic mechanism of action is not fully understood, but they may affect prostaglandin activity in the brain. Clinically, steroids quantitatively decrease or eliminate episodes of N&V and may improve patients’ mood, producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). Steroids are sometimes used as single agents against mildly emetogenic chemotherapy but are more often used in antiemetic drug combinations.[101,102][Level of evidence: I];[103]

Steroids are given orally or intravenously before chemotherapy and may be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice for N&V in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally or intravenously in the dose range of 8 mg to 40 mg (pediatric dose, 0.25–0.5 mg/kg).[104,105] Methylprednisolone is also administered orally or intravenously at doses and schedules that vary from 40 mg to 500 mg every 6 to 12 hours for up to 20 doses.[102,106]

Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[107–109]

  • Immunosuppression.
  • Proximal muscle weakness (especially involving the thighs and upper arms).
  • Aseptic necrosis of the long bones.
  • Cataract formation.
  • Hyperglycemia and exacerbation of preexisting diabetes or escalation of subclinical diabetes to clinical pathology.
  • Adrenal suppression with hypocortisolism.
  • Lethargy.
  • Weight gain.
  • GI irritation.
  • Insomnia.
  • Anxiety.
  • Mood changes.
  • Psychosis.

A study that examined chemotherapy in a group of patients with ovarian cancer found that short-term use of glucocorticoids as antiemetics had no negative effects on outcomes (e.g., overall survival or efficacy of chemotherapy).[110] As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3 receptor–blocking agents.[107,111] If administered intravenously, dexamethasone may be given over 10 to 15 minutes because rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[112–115]

Benzodiazepines

Benzodiazepines, such as lorazepam and alprazolam, are valuable adjuncts in the prevention and treatment of anxiety and the symptoms of anticipatory N&V associated with chemotherapy, especially with the highly emetogenic regimens given to children.[107–109] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents, so they are adjuncts to other antiemetic agents in antiemetic prophylaxis and treatment.[116] Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, these drugs markedly decrease the severity of EPS, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

The adverse effects of lorazepam include sedation, perceptual and vision disturbances, anterograde amnesia, confusion, ataxia, and depressed mental acuity.[117];[118][Level of evidence: I];[119,120] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.[19]

Olanzapine

Olanzapine is an antipsychotic in the thienobenzodiazepine drug class that blocks multiple neurotransmitters: dopamine at D1, D2, D3, and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors.[121] Common side effects include the following:[122,123]

  • Sedation.
  • Dry mouth.
  • Increased appetite.
  • Weight gain.
  • Postural hypotension.
  • Dizziness.

Olanzapine’s activity at multiple receptors, particularly at the D2 and 5-HT3 receptors that appear to be involved in N&V, suggests that it may have significant antiemetic properties.[124][Level of evidence: II] Subsequent studies have shown its effectiveness as a CINV antiemetic.[125,126][Level of evidence: II] A large study [127][Level of evidence: I] demonstrated that in patients receiving either highly emetogenic chemotherapy or moderately emetogenic chemotherapy, the addition of olanzapine to azasetron and dexamethasone improved the CR of delayed CINV.

A randomized, double-blind, phase III trial evaluated olanzapine versus placebo in addition to standard antiemetics for the prevention of CINV associated with highly emetogenic chemotherapy.[20][Level of evidence: I] Chemotherapy-naïve patients receiving either (1) cisplatin at least 70 mg/m2 of body surface area (BSA) with or without additional agents or (2) doxorubicin 60 mg/m2 of BSA with cyclophosphamide 600 mg/m2 of BSA were randomly assigned to receive olanzapine 10 mg orally on days 1 through 4 or matching placebo with guideline-directed antiemetics. The antiemetic regimen included an NK-1 antagonist (fosaprepitant or aprepitant), 5-HT3 receptor antagonist (palonosetron, granisetron, or ondansetron), and dexamethasone 12 mg on day 1, followed by 8 mg orally daily on days 2 through 4. Patients were stratified by sex, chemotherapy regimen, and the specific 5-HT3 receptor antagonist chosen. The primary endpoint, no nausea, was defined as a score of 0 on the visual analog scale of 0 to 10 and assessed at three time points postchemotherapy:

  • Early, 0 to 24 hours.
  • Later, 25 to 120 hours.
  • Overall, 0 to 120 hours.

The percentage of patients experiencing no nausea was significantly higher in the olanzapine group than in the placebo group at the early (74% vs. 45%; P = .002), later (42% vs. 25%; P = .002), and overall time points (37% vs. 22%; P = .002). CR rate and freedom from clinically significant nausea (a score lower than 3 on the visual analog scale of 0–10) were also significantly improved with the addition of olanzapine at all time points. Patients receiving olanzapine reported increased sedation from baseline on day 2, which resolved on days 3 through 5. On the basis of these data and additional clinical trials, olanzapine appears to be safe and effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[128,129]

Other Pharmacological Agents

Cannabis

The plant Cannabis contains more than 60 different types of cannabinoids, or components that have physiological activity. The most popular, and perhaps the most psychoactive, is delta-9-tetrahydrocannabinol (delta-9-THC).[130] There are two FDA-approved Cannabis products for CINV:

  • Dronabinol (a synthetic delta-9-THC), as prophylaxis for CINV, 5 mg/m2 orally 1 to 3 hours before chemotherapy and every 2 to 4 hours after chemotherapy, for a total of no more than 6 doses per day.
  • Nabilone, for CINV that has failed to respond to other antiemetics, 1 to 2 mg orally twice a day.

With respect to CINV, Cannabis products probably target cannabinoid-1 and cannabinoid-2 receptors, which are in the CNS.[131]

Much of the research on agents in this class, conducted in the late 1970s and 1980s, compared nabilone, dronabinol, or levonantradol to older antiemetic agents that targeted the dopamine receptor, such as prochlorperazine (Compazine) and metoclopramide (Reglan).[132–136] This group of studies demonstrated that cannabinoids were as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or were more effective than placebo.[130] Side effects included euphoria, dizziness, dysphoria, hallucinations, and hypotension.[130] Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer nabilone because of the side effects.[132]

Since the 1990s, research in N&V has elucidated newer and more physiological targets, namely 5-HT3 and NK-1 receptors. Subsequently, 5-HT3 and NK-1 receptor antagonists have become standard prophylactic therapy for CINV. Few studies have investigated the role of Cannabis extract and cannabinoids with these newer agents, so only limited conclusions can be drawn. In published trials, however, Cannabis extract and cannabinoids have not demonstrated more efficacy than 5-HT3 receptor antagonists, and synergistic or additive effects have not been fully investigated.[137,138]

In summary, Cannabis and cannabinoids’ role in the prevention and treatment of CINV is not known. Discussions with patients about their use may include responses to available agents, known side effects of Cannabis, and an assessment of the risks versus benefits of this therapy.[139] For more information, see Cannabis and Cannabinoids.

Ginger

There are conflicting data on the efficacy of ginger for prophylaxis of CINV. A phase III, randomized, dose-finding trial of 576 patients with cancer evaluated 0.5 g, 1 g, and 1.5 g of ginger versus placebo in twice-a-day dosing for the prevention of acute nausea (defined as day 1 postchemotherapy). Patients experienced some level of nausea (as measured on an 11-point scale) caused by their current chemotherapy regimen, despite standard prophylaxis with a 5-HT3 receptor antagonist. Patients began taking ginger or placebo capsules 3 days before each chemotherapy treatment and continued them for 6 days. For average nausea severity, 0.5 g of ginger was significantly better than placebo. For maximum nausea severity, both 0.5 g and 1 g were significantly better than placebo. Effects for delayed N&V were not significant. This trial did not control for emetogenicity of the chemotherapy regimens. Adverse events were infrequent and were not severe.[23]

Conversely, data on ginger used to prevent N&V have not been as promising. A randomized, double-blind, placebo-controlled study evaluated the use of ginger 160 mg per day in patients receiving high-dose cisplatin (>50 mg/m2). Patients (N = 251) were assigned to receive either ginger or placebo. The incidence of delayed nausea, intercycle nausea, and anticipatory nausea did not differ between the two treatment arms.[140]

Multiday Chemotherapy

Regimens that include chemotherapy doses on multiple sequential days (multiday chemotherapy) present a unique challenge to preventing CINV because after the first dose of chemotherapy, nausea may be both acute and delayed. Although there is no standard antiemetic regimen for multiday chemotherapy, a corticosteroid and a 5-HT3 receptor antagonist should be given with each day of highly and moderately emetogenic chemotherapy.[7,141] Evidence demonstrates benefit for the addition of an NK-1 antagonist to highly and moderately emetogenic multiday chemotherapy.[2,7,13,141] The choice of antiemetic drugs and their schedule should be matched to the emetogenicity of the individual chemotherapy agents and their sequence. In addition, the length of delayed nausea varies and will depend on the emetogenicity of the last day’s chemotherapy.

Dexamethasone is scheduled on each day of a multiday chemotherapy regimen and for 2 to 3 days after if there is risk of delayed nausea. Additional dexamethasone is not necessary if the chemotherapy regimen contains a corticosteroid. It is not known whether dexamethasone 20 mg given each day of a 5-day cisplatin regimen provides additional antiemetic benefit, and it may add toxicity.[13,142] Therefore, an alternative dexamethasone schedule (20 mg on days 1 and 2, followed by 8 mg twice daily on days 6 and 7, and 4 mg twice daily on day 8), based on the timing of CINV and to reduce the total steroid dose, has been studied in patients receiving 5-day cisplatin regimens.[12,13]

Standard antiemetic prophylaxis includes a 5-HT3 receptor antagonist given before the first chemotherapy dose each day of a multiday chemotherapy regimen.[2,7,13,141] No 5-HT3 receptor antagonist is favored over other agents in the class for multiday chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and higher receptor-binding affinity than other members in its class, allowing it to be given less frequently.[71] A prospective, uncontrolled trial demonstrated that palonosetron, as a single IV dose with dexamethasone 20 mg before two 3-day chemotherapy regimens, resulted in an 80% CR.[143] Palonosetron was also studied with dexamethasone as prophylaxis for a 5-day cisplatin-based regimen for germ cell tumors.[12] When palonosetron plus dexamethasone was given on days 1, 3, and 5, 51% of patients experienced no emesis on days 1 to 5, and 83% experienced no emesis on days 6 to 9.

Alternative methods of 5-HT3 receptor antagonist delivery have been studied. Granisetron as a 7-day continuous transdermal patch was compared with daily oral granisetron in patients receiving multiday chemotherapy in a double-blind, phase III, noninferiority study.[63] The patch demonstrated complete control in 60% of patients, while the oral formulation did so in 65% of patients, achieving noninferiority.

The NK-1 antagonist aprepitant and its IV formulation, fosaprepitant, have been studied with multiday chemotherapy in dosing schedules that differ from their FDA-approved schedules. A nonrandomized trial evaluated the use of aprepitant, granisetron, and dexamethasone for CINV prophylaxis with 3- and 5-day highly and moderately emetogenic chemotherapy.[144] Aprepitant was given at 125 mg orally before the first dose of chemotherapy, then 80 mg orally on each day of chemotherapy and for 2 following days (total, 5–7 days). CR was seen in 57.9% and 72.5% of patients receiving highly and moderately emetogenic chemotherapy, respectively. Similarly promising results were found in a subsequent single-arm trial looking at a 7-day oral aprepitant regimen with dexamethasone and a 5-HT3 receptor antagonist for 5-day cisplatin-based chemotherapy.[145]

A randomized, double-blind, placebo-controlled crossover trial of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone was conducted in patients receiving 5-day cisplatin-based chemotherapy for germ cell tumors.[86] Oral aprepitant 125 mg was given on day 3, followed by oral aprepitant 80 mg daily on days 4 to 7. More patients achieved CR with aprepitant than with placebo, 42% versus 13% (P < .001). IV fosaprepitant 150 mg given on days 3 and 5 was studied in a small phase II trial evaluating its use with a 5-HT3 receptor antagonist and dexamethasone in 5-day cisplatin-based chemotherapy.[146] Preliminary results showed a CR rate of 28.1%, lower than results of the oral aprepitant trial conducted by the same institution.

High-Dose Chemotherapy With Stem Cell Transplantation

Prevention of emesis during high doses of chemotherapy, with or without total-body irradiation, continues to be a challenging area of patient care.[147] Current guidelines address primarily single-day therapies. In addition, while emesis prevention for the multiple days of chemotherapy or radiation therapy used in this setting is based on single-day experiences, additional research is needed to improve symptom control for these patients.[147] This has led to the addition of NK-1 antagonists to the daily dosing of a serotonin antagonist plus dexamethasone.[147–149] Additional evidence is needed to determine optimal combinations as CR rates range as low as 30%.[149] Also, experience has primarily been with aprepitant. The newer NK-1 antagonists may offer additional benefit.

Overall, these antiemetic combinations are well tolerated, with most side effects involving the dexamethasone component; in addition, while drug interactions were originally a concern, they do not appear to be clinically significant.[150] Also, emesis is controlled to a much greater extent than is nausea, which continues to be challenging for many patients.[147,151] Finally, a randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of CINV in multiple myeloma patients receiving high-dose melphalan with autologous stem cell transplantation. A statistically positive benefit, without an increase in side effects, was seen in patients who received the three-drug regimen.[148]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  139. Coffman KL: The debate about marijuana usage in transplant candidates: recent medical evidence on marijuana health effects. Curr Opin Organ Transplant 13 (2): 189-95, 2008. [PUBMED Abstract]
  140. Bossi P, Cortinovis D, Fatigoni S, et al.: A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin. Ann Oncol 28 (10): 2547-2551, 2017. [PUBMED Abstract]
  141. Einhorn LH, Rapoport B, Koeller J, et al.: Antiemetic therapy for multiple-day chemotherapy and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer 13 (2): 112-6, 2005. [PUBMED Abstract]
  142. Baltzer L, Pisters KM, Kris MG, et al.: High dose ondansetron (OND) plus dexamethasone (DEX) for the prevention of nausea and vomiting with multiple day cisplatin chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-1607, 462, 1993.
  143. Lorusso V, Giampaglia M, Petrucelli L, et al.: Antiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapy. Support Care Cancer 20 (12): 3241-6, 2012. [PUBMED Abstract]
  144. Jordan K, Kinitz I, Voigt W, et al.: Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer 45 (7): 1184-7, 2009. [PUBMED Abstract]
  145. Olver IN, Grimison P, Chatfield M, et al.: Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support Care Cancer 21 (6): 1561-8, 2013. [PUBMED Abstract]
  146. Adra N, Albany C, Brames MJ, et al.: Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study. Support Care Cancer 24 (7): 2837-42, 2016. [PUBMED Abstract]
  147. Stiff PJ, Fox-Geiman MP, Kiley K, et al.: Prevention of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant 19 (1): 49-55.e1, 2013. [PUBMED Abstract]
  148. Schmitt T, Goldschmidt H, Neben K, et al.: Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial. J Clin Oncol 32 (30): 3413-20, 2014. [PUBMED Abstract]
  149. Sakurai M, Mori T, Kato J, et al.: Efficacy of aprepitant in preventing nausea and vomiting due to high-dose melphalan-based conditioning for allogeneic hematopoietic stem cell transplantation. Int J Hematol 99 (4): 457-62, 2014. [PUBMED Abstract]
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  151. Yeh SP, Lo WC, Hsieh CY, et al.: Palonosetron and dexamethasone for the prevention of nausea and vomiting in patients receiving allogeneic hematopoietic stem cell transplantation. Support Care Cancer 22 (5): 1199-206, 2014. [PUBMED Abstract]

Nonpharmacological Management of Nausea and Vomiting

Nonpharmacological strategies are also used to manage nausea and vomiting (N&V). These include the following:

Guided imagery, hypnosis, and systematic desensitization as means to progressive muscle relaxation have been the most frequently studied treatments for anticipatory N&V (ANV). They are the recommended treatments for this classically conditioned response. For more information, see the Treatment of ANV section.

Radiation-Induced Nausea and Vomiting

Radiation therapy (RT) is an important cause of nausea and vomiting (N&V) in patients with cancer. Observational studies suggest that some degree of N&V occurs in 80% of patients undergoing RT.[1] Risk factors for developing N&V are known. Radiation-induced N&V (RINV) worsen quality of life, leading to treatment delays and cancelled appointments and compromising cancer control.[2,3]

Epidemiology

Two large prospective observational studies provide information on the frequency of RINV and antiemetic measures. The Italian Group for Antiemetic Research in Radiotherapy analyzed the incidence of RINV in 1,020 patients receiving various kinds of RT.[4] Overall, 28% of patients reported nausea, vomiting, or both. The median time to the first episode of vomiting was 3 days. Antiemetic drugs were administered to 17% of the patients, including 12% treated prophylactically and 5% given rescue therapy. In a second cohort of 368 patients receiving RT, the overall incidence rate for nausea was 39% and for vomiting, 7%.[5] Nausea was more frequent in those receiving RT to the lower abdomen or pelvis (66%), compared with patients receiving RT to the head-and-neck area (48%). Antiemetics during RT are underprescribed.[6]

Pathophysiology

The pathophysiology of RINV is incompletely understood. Serotonin, substance P, and dopamine are neurotransmitters involved in radiation-induced emesis.[7] RINV bears a close similarity to chemotherapy-induced N&V (CINV). The effectiveness of serotonin antagonists in RINV supports a role for serotonin in radiation-induced emesis.[7] Substance P antagonists have not been used in RINV as extensively as in CINV. Preclinical work suggests a role for substance P in RINV.[8] Substance P antagonists are only beginning to be studied for RINV. Substance P may play a role in prolonged N&V after the administration of RT.

Risk Stratification

The incidence and severity of RINV are determined by:

  • Radiation site.
  • Volume.
  • Fractionation schedule.
  • Single and total dose.

The most important factor appears to be the radiation field. The risk of N&V for a patient being treated with RT depends on multiple other factors in addition to the emetogenicity of the specific RT regimen. Patient-specific factors include the following:[3]

  • Simultaneous administration of chemotherapy.
  • Age.
  • Gender.
  • Alcohol consumption.
  • Anxiety.
  • Previous experience of RINV or CINV.

Prevention and Treatment of RINV

The body of literature describing treatments for RINV is much smaller than that for CINV.[9] Most of the studies were for patients with moderate- to high-risk features for RINV.

Antiemetic therapy: Prevention and Treatment of N&V

Several studies show the superiority of serotonin antagonists for the prophylaxis of RINV.[10–15] Ondansetron and dolasetron showed superiority over placebo or metoclopramide. Dosing of the serotonin antagonists have been single-dose pretreatment or for consecutive days (up to 5–7 days total). Most studies have been conducted in patients at moderate to high risk of RINV.

Recommended dosing is ondansetron 8 mg, regardless of schedule given.[3] Granisetron dosing is 2 mg orally per day.[3] A recent meta-analysis covering nine clinical trials showed differing rates of control when emesis versus nausea is considered. Compared with placebo, fewer patients had residual emesis (40% vs. 57%; relative risk [RR], 0.7), and fewer patients required rescue medication (6.5% vs. 36%; RR, 0.18).[16] The control of nausea seems to be more difficult. Most patients developed RT-induced nausea despite treatment (70% vs. 83% with placebo; RR, 0.84).[17] In summary, these trials show that patients receiving upper-abdomen irradiation are more likely to control RINV with 5-hydroxytryptamine-3 (5-HT3) receptor antagonists than metoclopramide, phenothiazines, or placebo.[10–15]

The adverse effects of 5-HT3 receptor antagonists are generally mild, consisting mainly of headache, constipation, and asthenia.[18] Randomized trials in RINV have examined the use of different 5-HT3 receptor antagonists, but there are no data comparing them and no consensus on optimal dosing for RINV.[19] A systematic review of 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT. Optimal duration and timing of 5-HT3 use before, during, and after RT administration needs to be determined.[20] With regard to palonosetron, the appropriate dosing and frequency in the RINV setting are still unclear, with once-weekly dosing possible when the drug is combined with other agents.[21]

Corticosteroids

Corticosteroids are an attractive therapeutic antiemetic option because of their widespread availability and low cost. For short-term use, the side effects are few and do not outweigh the benefit of these agents. One randomized trial showed that dexamethasone was significantly more effective than placebo in patients receiving RT to the upper abdomen.[22] Combining corticosteroids with a 5-HT3 receptor antagonist was assessed in a well-designed randomized trial, in which a 5-day course of dexamethasone plus ondansetron was compared with ondansetron plus placebo in 211 patients who received RT to the upper abdomen.[23] During the first 5 days, there was a statistically nonsignificant trend toward complete control of nausea (50% vs. 38% with placebo) and vomiting (78% vs. 71%), which was the primary objective of the trial. The effects of dexamethasone extended beyond the initial 5-day period, and significantly more patients had complete control of emesis over the entire course of RT (23% vs. 12% with placebo), a secondary objective of the trial. The addition of dexamethasone has a modest effect on RINV and is potentially a useful addition to a 5-HT3 receptor antagonist in this setting.[23]

Neurokinin-1 (NK-1) receptor antagonists

NK-1 receptor antagonists have an established role in the management of CINV; however, no studies have evaluated their impact solely on the risk of RINV. Although preclinical data indicate that RINV is mediated in part by substance P,[8] recommendation of these agents is premature, and NK-1 receptor antagonists are not included in the antiemetic guidelines for RINV.[3] A phase III, randomized, placebo-controlled trial compared an NK-1 receptor antagonist, fosaprepitant, combined with palonosetron and dexamethasone, with palonosetron and dexamethasone alone in the prevention of N&V in patients who received concomitant RT and cisplatin.[21][Level of evidence: I] Patients received fractionated radiation therapy with weekly cisplatin, 40 mg/m2. All patients received dexamethasone on the same schedule: 16 mg on day 1, 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. More patients who received the three-drug regimen reached a complete response: 65.7% for the fosaprepitant group and 48.7% for the placebo group.

Fosaprepitant has also been compared with olanzapine for the prevention of N&V in patients with head and neck or esophageal cancer who received RT concurrently with highly emetogenic chemotherapy.[24] For those who received olanzapine, palonosetron, and dexamethasone (OPD), dosing was as follows: dexamethasone 20 mg and palonosetron 0.25 mg intravenously (IV) on day 1 of chemotherapy, and olanzapine 10 mg on days 1 to 4 of chemotherapy. For those who received fosaprepitant, palonosetron, and dexamethasone (FPD), dosing was as follows: dexamethasone 12 mg, palonosetron 0.25 mg IV, and fosaprepitant 150 mg IV on day 1 of chemotherapy, followed by dexamethasone 4 mg bid on days 2 to 3 of chemotherapy. Complete response was similar between the two groups, with a rate of 76% overall in the OPD arm and 74% overall in the FPD arm. This suggests that NK-1 receptor antagonists may play a role in patients receiving highly emetogenic chemotherapy.[24]

Other agents

Older, less-specific antiemetic drugs, such as prochlorperazine, metoclopramide, and cannabinoids, have shown limited efficacy in the prevention or treatment of RINV, although they may have a role in treating patients with milder symptoms and as rescue agents.[25]

Duration of Prophylaxis

The appropriate duration of antiemetic prophylaxis for patients receiving fractionated RT is not clear. There have been no randomized trials using 5-HT3 receptor antagonists that compared a 5-day course of treatment with a more protracted course.[7] A systematic review that included 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT.[20]

Rescue Therapy

Studies suggest the benefit of 5-HT3 receptor antagonists once nausea or vomiting occurs, but there are no trials specifically in this setting.[26] The emerging role of olanzapine in breakthrough emesis in patients with CINV has not been studied in RINV.[27]

Guidelines and Patient Management

For patients at high risk of developing RINV, prophylaxis with a 5-HT3 receptor antagonist is recommended in the clinical practice guidelines from both MASCC and ASCO. Based on results from patients receiving highly emetogenic chemotherapy, the addition of dexamethasone to the 5-HT3 receptor antagonist is suggested. The antiemetic clinical practice guidelines from both MASCC and ASCO also recommend that patients receiving moderately emetogenic RT be administered prophylaxis with a 5-HT3 receptor antagonist, with or without a short course of dexamethasone.[7] There are no fully published comparative clinical trials on the use of NK-1 receptor antagonists in preventing RINV; therefore, its use cannot be recommended.

Antiemetic dosing suggestions for the prevention of RINV are summarized in Table 6.

Table 6. Antiemetic Dosing for Radiation Therapya
Drug Category Antiemetic Dose Comment Reference
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; IV = intravenously; PO = by mouth; prn = as needed; RT = radiation therapy; TBI = total-body irradiation; tid = 3 times a day.
aAdapted from Roila et al.[3] and Hesketh et al.[28]
Serotonin (5-HT3) receptor antagonists Granisetron 2 mg PO daily   [14][Level of evidence: I]
Ondansetron 8 mg PO or 0.15 mg/kg IV daily bid–tid with TBI [19][Level of evidence: I]
Palonosetron 0.25 mg IV or 0.5 mg PO Not studied in RT; no data available on frequency of administration [28]
Dolasetron 100 mg PO only   [11][Level of evidence: I]
Corticosteroids Dexamethasone 4 mg PO or IV During fractions 1–5 [23][Level of evidence: I]
Dopamine receptor antagonists Metoclopramide 20 mg PO prn during minimal-emetic-risk RT; inferior to 5-HT3 receptor antagonists [19][Level of evidence: I]
Prochlorperazine 10 mg PO or IV prn during minimal-emetic-risk RT [28]
References
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  2. Maranzano E: Radiation-induced emesis: a problem with many open questions. Tumori 87 (4): 213-8, 2001 Jul-Aug. [PUBMED Abstract]
  3. Roila F, Molassiotis A, Herrstedt J, et al.: 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol 27 (suppl 5): v119-v133, 2016. [PUBMED Abstract]
  4. Maranzano E, De Angelis V, Pergolizzi S, et al.: A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres. Radiother Oncol 94 (1): 36-41, 2010. [PUBMED Abstract]
  5. Enblom A, Bergius Axelsson B, Steineck G, et al.: One third of patients with radiotherapy-induced nausea consider their antiemetic treatment insufficient. Support Care Cancer 17 (1): 23-32, 2009. [PUBMED Abstract]
  6. Horiot JC: Prophylaxis versus treatment: is there a better way to manage radiotherapy-induced nausea and vomiting? Int J Radiat Oncol Biol Phys 60 (4): 1018-25, 2004. [PUBMED Abstract]
  7. Feyer P, Jahn F, Jordan K: Radiation induced nausea and vomiting. Eur J Pharmacol 722: 165-71, 2014. [PUBMED Abstract]
  8. Yamamoto K, Nohara K, Furuya T, et al.: Ondansetron, dexamethasone and an NK1 antagonist block radiation sickness in mice. Pharmacol Biochem Behav 82 (1): 24-9, 2005. [PUBMED Abstract]
  9. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015. [PUBMED Abstract]
  10. Aass N, Håtun DE, Thoresen M, et al.: Prophylactic use of tropisetron or metoclopramide during adjuvant abdominal radiotherapy of seminoma stage I: a randomised, open trial in 23 patients. Radiother Oncol 45 (2): 125-8, 1997. [PUBMED Abstract]
  11. Bey P, Wilkinson PM, Resbeut M, et al.: A double-blind, placebo-controlled trial of i.v. dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer 4 (5): 378-83, 1996. [PUBMED Abstract]
  12. Volk A, Kersting S, Konopke R, et al.: Surgical therapy of intrapancreatic metastasis from renal cell carcinoma. Pancreatology 9 (4): 392-7, 2009. [PUBMED Abstract]
  13. Franzén L, Nyman J, Hagberg H, et al.: A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol 7 (6): 587-92, 1996. [PUBMED Abstract]
  14. Lanciano R, Sherman DM, Michalski J, et al.: The efficacy and safety of once-daily Kytril (granisetron hydrochloride) tablets in the prophylaxis of nausea and emesis following fractionated upper abdominal radiotherapy. Cancer Invest 19 (8): 763-72, 2001. [PUBMED Abstract]
  15. Priestman TJ, Dunn J, Brada M, et al.: Final results of the Royal College of Radiologists’ trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol (R Coll Radiol) 8 (5): 308-15, 1996. [PUBMED Abstract]
  16. Priestman TJ, Roberts JT, Upadhyaya BK: A prospective randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol (R Coll Radiol) 5 (6): 358-63, 1993. [PUBMED Abstract]
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  18. Goodin S, Cunningham R: 5-HT(3)-receptor antagonists for the treatment of nausea and vomiting: a reappraisal of their side-effect profile. Oncologist 7 (5): 424-36, 2002. [PUBMED Abstract]
  19. Salvo N, Doble B, Khan L, et al.: Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials. Int J Radiat Oncol Biol Phys 82 (1): 408-17, 2012. [PUBMED Abstract]
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Pediatric Chemotherapy-Induced Acute Nausea and Vomiting

Pediatric Guidelines for Acute Nausea and Vomiting (N&V)

Chemotherapy-induced N&V (CINV) is an important problem in the pediatric population. As in adults, nausea in children is more of a problem than vomiting. Parents of children who received active antineoplastic therapy in Ontario, Canada, identified nausea as the fourth most prevalent and bothersome treatment-related symptom.[1] Current approaches to prevent CINV are based on an accurate description of the potential of antineoplastic therapies to cause N&V. Current recommendations, based on published guidelines,[2] include patients aged 1 month to 18 years who are about to receive their first-ever course of antineoplastic therapy. These recommendations focus on the prevention of acute CINV (i.e., within 24 hours of administration of an antineoplastic agent).

Guidelines recommend that optimal control of acute CINV be defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention, and no nausea-related change in the child’s usual appetite and diet. This level of CINV control is to be achieved on each day that antineoplastic therapy is administered and for 24 hours after administration of the last agent in the antineoplastic therapy cycle.

Emetic Risk

In children receiving antineoplastic agents who were not given antiemetic prophylaxis or who were given ineffective prophylaxis, expected rates of complete CINV control were as follows:[2]

  • High emetic risk, less than 10%.
  • Moderate emetic risk, 10% to less than 30%.
  • Low emetic risk, 30% to less than 90%.
  • Minimal emetic risk, more than 90%.

The expected rate of complete CINV control in children receiving antiemetic prophylaxis (5-hydroxytryptamine-3 [5-HT3] receptor antagonist with or without dexamethasone) is more than 70% to 80%.[2] Each chemotherapy agent carries an inherent risk of emesis, which is the first issue to consider when planning chemotherapy treatment. For more information about preventing acute or delayed CINV, see Table 5.

Acute Chemotherapy-Induced Nausea and Vomiting—Antiemetic Prophylaxis

Highly emetogenic chemotherapy

Guidelines [2,3] recommend that children aged 6 months and older who are receiving antineoplastic agents of high emetic risk that are not known or suspected to interact with aprepitant receive aprepitant, a 5-HT3 receptor antagonist, and dexamethasone. Children older than 6 months who cannot receive dexamethasone should receive a 5-HT3 receptor antagonist plus aprepitant. Children who cannot receive aprepitant should receive a 5-HT3 receptor antagonist plus dexamethasone.[4][Level of evidence: IV]

Moderately emetogenic chemotherapy

Children receiving antineoplastic agents of moderate emetogenicity should receive ondansetron, granisetron, or palonosetron plus dexamethasone. Children aged 6 months and older and whose antineoplastic agents do not interact with aprepitant and who cannot receive dexamethasone should receive a 5-HT3 receptor antagonist plus aprepitant.[3,4][Level of evidence: IV]

Low emetogenic chemotherapy

Children receiving antineoplastic agents of low emetogenicity should receive a 5-HT3 receptor antagonist.[3]

Minimal emetogenic potential

Children receiving antineoplastic agents of minimal emetogenicity should receive no routine prophylaxis.[3]

Other Antiemetic Modalities

Current consensus is that the following modalities may be effective in children receiving antineoplastic agents:[2]

  • Acupuncture.
  • Acupressure.
  • Guided imagery.
  • Music therapy.
  • Progressive muscle relaxation.
  • Psychoeducational support and information.

In addition, virtual reality may convey some benefit. Other recommendations (low level of evidence) include the following:

  • Eating smaller, more-frequent meals.
  • Reducing food aromas and other stimuli with strong odors.
  • Avoiding foods that are spicy, fatty, or highly salty.
  • Taking antiemetics before meals so that the effect is present during and after meals.
  • Using measures and foods (e.g., “comfort foods”) that previously helped minimize nausea.

Despite a lack of strong evidence, most experts think that these recommendations are unlikely to result in undesirable effects or to adversely affect quality of life, and they may convey benefit.[2]

Antiemetics

Prophylaxis with a 5-HT3 receptor antagonist alone leads to poor CINV control in patients receiving antineoplastic agents of moderate and high emetic risk. A synthesis of three studies that evaluated alternative antiemetic agents (chlorpromazine and metoclopramide) in children receiving highly emetogenic chemotherapy observed a complete CINV control rate of 9% (95% confidence interval: 0, 20).[2] When corticosteroids are contraindicated, it is recommended that nabilone or chlorpromazine be administered together with ondansetron or granisetron to children receiving highly emetogenic chemotherapy. Metoclopramide is a third option for children receiving moderately emetogenic chemotherapy. Corticosteroids combined with a serotonin antagonist are recommended for patients receiving highly and moderately emetogenic chemotherapy.[5]

Antiemetic dosing suggestions for pediatric patients are summarized in Table 7.

Table 7. Pediatric Antiemetic Dosing
Drug Category Medication Dose Available Route Comment Reference
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; BSA = body surface area; EPS = extrapyramidal symptoms; IM = intramuscular; IV = intravenous; NK-1 = neurokinin-1; PO = oral; PR = rectal; prn = as needed; qd = every day; SL = sublingual; tid = 3 times a day.
aPalonosetron prescribing information lists the pediatric maximum dose at 1.5 mg.
Phenothiazines Chlorpromazine 0.5 mg/kg/dose q6h; may increase to 1 mg/kg/dose q6h; maximum dose: 50 mg IV Prolongs QTc interval; use with 5-HT3 receptor antagonist when corticosteroid contraindicated; dose adjustments based on efficacy and sedation [6]; [2][Level of evidence: IV]; [7][Level of evidence: I]
Prochlorperazine 9–13 kg: 2.5 mg PO qd–bid; maximum dose: 7.5 mg/d PO, IM, IV Less sedation, but increased risk of EPS [6]; [8][Level of evidence: I]
13–18 kg: 2.5 mg PO bid–tid; maximum dose: 10 mg/d
18–39 kg: 2.5 mg tid or 5 mg bid; maximum dose: 15 mg/d
Promethazine Age >2 y: 0.25–1 mg/kg/dose q4–6h; maximum dose: 25 mg PO, IM, IV, PR Vesicant [6]
Substituted benzamides Metoclopramide Moderately emetogenic chemotherapy: 1 mg/kg/dose IV once prechemotherapy, then 0.0375 mg/kg/dose PO q6h PO, IM, IV EPS associated with higher doses; pretreat with benztropine or diphenhydramine to prevent EPS; enhances gastric emptying [6]; [9][Level of evidence: I]
Serotonin (5-HT3) receptor antagonists Granisetron 40 μg/kg IV daily; 40 μg/kg PO q12h; maximum: 1 mg/dose IV, PO   [10][Level of evidence: I]
Ondansetron Age 0–<12 y: 0.15 mg/kg/dose (5 mg/m2/dose) prechemotherapy, then q8h for highly emetogenic or q12h for moderately emetogenic chemotherapy PO, IV Avoid IV doses >16 mg due to QTc prolongation; age >12 y: follow adult dosing [6]; [2][Level of evidence: IV]
Low emetogenic chemotherapy: 0.3 mg/kg/dose (10 mg/m2/dose) once prechemotherapy
Maximum PO dose: 24 mg; maximum IV dose: 16 mg
Palonosetron Age 1 mo–17 y: 20 μg/kg; maximum dose: 0.75 mga IV, PO Due to pediatric half-life of 30 h, administered q2–3d during multiday chemotherapy [2][Level of evidence: I]; maximum dose: [11]
Substance P antagonists (NK-1 receptor antagonists) Aprepitant Capsule: Age >12 y: 125 mg prechemotherapy day 1, then 80 mg qd x2 d PO CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [12][Level of evidence: I]
Suspension: Age 6 mo–12 y (and >6 kg): 3 mg/kg prechemotherapy day 1, then 2 mg/kg qd x2 d Suspension: Maximum dose day 1: 125 mg; maximum dose days 2–3: 80 mg
Fosaprepitant Age 13–17 y: 150 mg IV CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [13][Level of evidence: III]
Corticosteroids Dexamethasone Highly emetogenic chemotherapy: 6 mg/m2/dose q6h PO, IV May be omitted in some brain tumor, osteosarcoma, and carcinoma protocols due to fear of reducing cytotoxic effects of chemotherapy [6]; [2][Level of evidence: IV]
Moderately emetogenic chemotherapy: BSA ≤0.6 m2: 2 mg q12h Combined with 5-HT3 receptor antagonist
BSA >0.6 m2: 4 mg q12h When given with aprepitant or fosaprepitant, reduce dose by 50%
Maximum: 20 mg/dose Most effective for delayed nausea
Methylprednisolone 4–10 mg/kg/dose PO, IV Given with 5-HT3 receptor antagonist [14,15][Level of evidence: I]
Benzodiazepines Lorazepam Anticipatory: 0.02–0.05 mg/kg/dose (maximum: 2 mg/dose) once at bedtime the night before chemotherapy and once prechemotherapy PO, SL, IM, IV Most-commonly used drug in class [6]
Breakthrough: 0.02–0.05 mg/kg/dose IV (maximum: 2 mg) q6h prn [16][Level of evidence: IV]
Atypical antipsychotics Olanzapine 0.1–0.14 mg/kg/dose qd; maximum: 10 mg PO   [17][Level of evidence: III]
Other pharmacological agents Dronabinol Age 6–18 y: 2.1 mg/m2 1–3 h prechemotherapy PO Single-institution experience only; benefit of appetite stimulant properties [18][Level of evidence: III]
Nabilone Age >4 y: PO May be continued up to 48 h postchemotherapy; has not been compared with 5-HT3 receptor antagonist with or without corticosteroid; use with 5-HT3 receptor antagonist when corticosteroid contraindicated [19][Level of evidence: I]; [8]
<18 kg: 0.5 mg q12h
18–30 kg: 1 mg q12h
>30 kg: 1 mg q8–12h
Maximum dose: 0.06 mg/kg/d

Multiagent, single-day chemotherapy regimens

Experience in pediatrics and guidelines recommend basing the emetogenicity of combination antineoplastic regimens on that of the agent of highest emetic risk.[20] The emetogenicity of the antineoplastic combinations in the following list appears to be higher than would be appreciated by assessment of the emetic risk of the individual agents.[21]

High Level of Emetic Risk (>90% Frequency of Emesis in Absence of Prophylaxis)

  • Cyclophosphamide + anthracycline.
  • Cyclophosphamide + etoposide.
  • Cytarabine (150–200 mg/m2) + daunorubicin.
  • Cytarabine (300 mg/m2) + etoposide.
  • Cytarabine (300 mg/m2) + teniposide.
  • Doxorubicin + ifosfamide.
  • Doxorubicin + methotrexate (5 g/m2).
  • Etoposide + ifosfamide.
References
  1. Dupuis LL, Milne-Wren C, Cassidy M, et al.: Symptom assessment in children receiving cancer therapy: the parents’ perspective. Support Care Cancer 18 (3): 281-99, 2010. [PUBMED Abstract]
  2. Dupuis LL, Boodhan S, Holdsworth M, et al.: Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60 (7): 1073-82, 2013. [PUBMED Abstract]
  3. Dupuis LL, Sung L, Molassiotis A, et al.: 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 25 (1): 323-331, 2017. [PUBMED Abstract]
  4. Patel P, Robinson PD, Cohen M, et al.: Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: A clinical practice guideline. Pediatr Blood Cancer 69 (12): e30001, 2022. [PUBMED Abstract]
  5. White L, Daly SA, McKenna CJ, et al.: A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy. Pediatr Hematol Oncol 17 (6): 445-55, 2000. [PUBMED Abstract]
  6. Lexicomp Online. Hudson, Ohio: Lexi-Comp, Inc., 2021. Available online with subscription. Last accessed Feb. 9, 2024.
  7. Relling MV, Mulhern RK, Fairclough D, et al.: Chlorpromazine with and without lorazepam as antiemetic therapy in children receiving uniform chemotherapy. J Pediatr 123 (5): 811-6, 1993. [PUBMED Abstract]
  8. Chan HS, Correia JA, MacLeod SM: Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 79 (6): 946-52, 1987. [PUBMED Abstract]
  9. Köseoglu V, Kürekçi AE, Sarici U, et al.: Comparison of the efficacy and side-effects of ondansetron and metoclopramide-diphenhydramine administered to control nausea and vomiting in children treated with antineoplastic chemotherapy: a prospective randomized study. Eur J Pediatr 157 (10): 806-10, 1998. [PUBMED Abstract]
  10. Berrak SG, Ozdemir N, Bakirci N, et al.: A double-blind, crossover, randomized dose-comparison trial of granisetron for the prevention of acute and delayed nausea and emesis in children receiving moderately emetogenic carboplatin-based chemotherapy. Support Care Cancer 15 (10): 1163-8, 2007. [PUBMED Abstract]
  11. Kadota R, Shen V, Messinger Y: Safety, pharmacokinetics, and efficacy of palonosetron in pediatric patients: a multicenter, stratified, double-blind, phase 3, randomized study. [Abstract] J Clin Oncol 25 (18 suppl): A-9570, 2007.
  12. Kang HJ, Loftus S, Taylor A, et al.: Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 16 (4): 385-94, 2015. [PUBMED Abstract]
  13. Siddiqui MA, Ghaznawi HI: Some observations on intestinal parasites in Hajis visiting Saudi Arabia, during 1983 G (1403 H.) Pilgrimage. J Egypt Soc Parasitol 15 (2): 705-12, 1985. [PUBMED Abstract]
  14. Small BE, Holdsworth MT, Raisch DW, et al.: Survey ranking of emetogenic control in children receiving chemotherapy. J Pediatr Hematol Oncol 22 (2): 125-32, 2000 Mar-Apr. [PUBMED Abstract]
  15. Hirota T, Honjo T, Kuroda R, et al.: [Antiemetic efficacy of granisetron in pediatric cancer treatment–(2). Comparison of granisetron and granisetron plus methylprednisolone as antiemetic prophylaxis]. Gan To Kagaku Ryoho 20 (15): 2369-73, 1993. [PUBMED Abstract]
  16. Dupuis LL, Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 5 (9): 597-613, 2003. [PUBMED Abstract]
  17. Flank J, Thackray J, Nielson D, et al.: Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review. Pediatr Blood Cancer 62 (3): 496-501, 2015. [PUBMED Abstract]
  18. Elder JJ, Knoderer HM: Characterization of Dronabinol Usage in a Pediatric Oncology Population. J Pediatr Pharmacol Ther 20 (6): 462-7, 2015 Nov-Dec. [PUBMED Abstract]
  19. Dalzell AM, Bartlett H, Lilleyman JS: Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 61 (5): 502-5, 1986. [PUBMED Abstract]
  20. Dupuis LL, Boodhan S, Sung L, et al.: Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 57 (2): 191-8, 2011. [PUBMED Abstract]
  21. Holdsworth MT, Raisch DW, Frost J: Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 106 (4): 931-40, 2006. [PUBMED Abstract]

Pediatric Delayed Nausea and Vomiting

In adults, delayed nausea and vomiting (N&V) remains a significant problem, though strategies exist to control it. The nature and prevalence of delayed N&V in children after administration of antineoplastic agents have not been well described.[1] Additionally, most pediatric chemotherapy regimens give multiple days of chemotherapy, making the onset and duration of risk of delayed versus acute N&V unclear.

Research on chemotherapy-induced N&V (CINV) in children has been limited in part by the lack of assessment tools and the subjective nature of nausea. In the pediatric population, vomiting is more easily recognizable and measurable than nausea.[1] Difficulties in assessing nausea in young children may contribute to the common perception that young children experience CINV less frequently than do older children. In addition, caregivers may have a higher tolerance for vomiting in young children and may miss detecting nausea.[1] In view of these limitations, studies often use dietary intake to assess the extent of nausea.

Several investigators have attempted to determine the prevalence of delayed N&V in the pediatric population. One early study suggested a low incidence.[2] A large study assessed the nature and prevalence of delayed CINV in children.[1] Nausea was self-assessed daily using a numeric scale reflecting the effect of nausea on activities and a faces scale for children aged 3 to 6 years. Diet was also assessed daily. Results showed a 33% incidence of delayed vomiting in patients who received cyclophosphamide, cisplatin, or carboplatin and an 11% incidence in those who received other antineoplastic agents. No antiemetics were given on 412 (79%) of 522 study days. Nevertheless, on 381 (93%) of those 412 study days, patients were completely free from vomiting. Antiemetics were most often given as single agents (ondansetron, on 54 study days; dimenhydrinate, on 17 study days; dexamethasone, on 6 study days). Diet was not affected. The authors concluded that antineoplastic-induced delayed N&V may be less prevalent in children than in adults.[1] The high percentage of children who did not experience delayed vomiting may reflect a lack of significant emetogenic potential among many of the regimens in the study. In 100 of 174 chemotherapy cycles, no antiemetics were administered. In addition, there was no characterization of antiemetic response in moderate and severe chemotherapy regimens.

Another study evaluated the incidence of delayed N&V in pediatric patients receiving moderately and highly emetogenic chemotherapy as well as premedications (ondansetron alone or with dexamethasone, depending on a treatment’s emetogenic potential).[3] Investigators measured nausea severity and duration, vomiting severity, the number of vomiting episodes, interference with daily activities, and assessment of appetite. The authors found that delayed N&V occurred with both moderately and highly emetogenic regimens. The severity of N&V varied between the moderately emetogenic and highly emetogenic chemotherapy regimens. In addition, toddlers had better antiemetic control than older children, which may be the result of anxiety differences between the age groups. The reasons for toddler patients’ greater complete control are unclear but are consistent with a previous study of N&V control rates in children.[4] Anxiety and patient perception may be important contributors to N&V in older children; the authors found a relationship between control of acute N&V and the occurrence of delayed N&V.

Another study suggests a higher incidence of delayed N&V than was previously found in a pediatric population.[5] In 40 pediatric cancer patients receiving chemotherapy, N&V was measured from the child’s perspective using the Adapted Rhodes Index of Nausea and Vomiting for Pediatrics; from the primary caregiver’s perspective using the Adapted Rhodes Index of Nausea and Vomiting for Parents; and from the nurses’ perspective using the National Cancer Institute Nausea and Vomiting Grading Criteria. The highest frequency of nausea occurred in the delayed period, with 60% of patients (n = 24) reporting delayed nausea. The authors concluded that CINV occurred throughout the chemotherapy course, with delayed N&V occurring most frequently and with greater severity and distress. Delayed N&V in the pediatric population requires further study.

Because well-designed studies on the prevention of delayed N&V in children are not available, the best available evidence comes from adult data and a pediatric clinical practice guideline.[6][Level of evidence: IV]; [7]

Delayed Chemotherapy-Induced Nausea and Vomiting—Antiemetic Prophylaxis

Highly emetogenic chemotherapy

Palonosetron should be considered the preferred 5-hydroxytryptamine-3 (5-HT3) receptor antagonist in the acute phase in patients at high risk of delayed phase CINV. Guidelines recommend that children who can receive aprepitant and dexamethasone continue to do so during the delayed phase. If dexamethasone cannot be used, aprepitant should be continued. If aprepitant cannot be used, dexamethasone should be continued. If olanzapine was started during the acute phase, it should be continued during the delayed phase.[6][Level of evidence: IV]

In a phase III, double-blind, randomized controlled trial, 128 patients aged 3 to 18 years receiving highly emetogenic chemotherapy were randomly assigned to receive intravenous ondansetron and dexamethasone plus olanzapine or placebo on days 1 and 2. More patients in the olanzapine group had complete control of vomiting in the delayed phase (73% vs. 48%; P = .005), although there was no difference in control in the acute phase or overall. More patients in the placebo group required rescue medications for vomiting than in the olanzapine group (29% vs. 14%; P = .025). Grade 1/2 sedation was greater in the olanzapine group than in the placebo group (46% vs. 14%).[8]

Moderately emetogenic chemotherapy

In the delayed phase, children receiving antineoplastic agents of moderate emetogenicity who received a 5-HT3 receptor inhibitor and dexamethasone in the acute phase should consider dexamethasone during the delayed phase.

Children receiving a 1-day regimen of antineoplastic agents of moderate emetogenicity who received a 5-HT3 receptor inhibitor and fosaprepitant or aprepitant in the acute phase should continue oral aprepitant in the delayed phase. Children receiving a multiday regimen of antineoplastic agents of moderate emetogenicity who received a 5-HT3 receptor inhibitor and fosaprepitant or aprepitant in the acute phase should consider not using oral aprepitant in the delayed phase.

Children receiving a 5-HT3 receptor inhibitor with olanzapine during the acute phase should consider continuing olanzapine during the delayed phase.[6][Level of evidence: IV]

Low emetogenic chemotherapy

Children receiving antineoplastic agents of low emetogenicity should not receive routine prophylaxis during the delayed phase.[6][Level of evidence: IV]

Minimal emetogenic potential

Children receiving antineoplastic agents of minimal emetogenicity should not receive routine prophylaxis during the delayed phase.[6][Level of evidence: IV]

References
  1. Dupuis LL, Lau R, Greenberg ML: Delayed nausea and vomiting in children receiving antineoplastics. Med Pediatr Oncol 37 (2): 115-21, 2001. [PUBMED Abstract]
  2. Foot AB, Hayes C: Audit of guidelines for effective control of chemotherapy and radiotherapy induced emesis. Arch Dis Child 71 (5): 475-80, 1994. [PUBMED Abstract]
  3. Holdsworth MT, Raisch DW, Frost J: Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 106 (4): 931-40, 2006. [PUBMED Abstract]
  4. Small BE, Holdsworth MT, Raisch DW, et al.: Survey ranking of emetogenic control in children receiving chemotherapy. J Pediatr Hematol Oncol 22 (2): 125-32, 2000 Mar-Apr. [PUBMED Abstract]
  5. Rodgers C, Kollar D, Taylor O, et al.: Nausea and vomiting perspectives among children receiving moderate to highly emetogenic chemotherapy treatment. Cancer Nurs 35 (3): 203-10, 2012 May-Jun. [PUBMED Abstract]
  6. Patel P, Robinson PD, Cohen M, et al.: Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: A clinical practice guideline. Pediatr Blood Cancer 69 (12): e30001, 2022. [PUBMED Abstract]
  7. Dupuis LL, Sung L, Molassiotis A, et al.: 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 25 (1): 323-331, 2017. [PUBMED Abstract]
  8. Moothedath AW, Meena JP, Gupta AK, et al.: Efficacy and Safety of Olanzapine in Children Receiving Highly Emetogenic Chemotherapy: A Randomized, Double-blind Placebo-controlled Phase 3 Trial. J Pediatr Hematol Oncol 44 (8): 446-453, 2022. [PUBMED Abstract]

Pediatric Anticipatory Nausea and Vomiting

Cancer patients who have received chemotherapy may experience nausea and vomiting (N&V) when anticipating further chemotherapy. Study differences in methodology, timing, and assessment instruments; small samples; and a focus on nausea or vomiting but not both has led to difficulties in capturing the prevalence of anticipatory N&V (ANV) in children. Accurate prevalence is also stymied by using parent or caregiver proxy reports of nausea and nonvalidated nausea assessment tools.

In patients receiving 5-hydroxytryptamine-3 (5-HT3) receptor antagonists and corticosteroids as antiemetic agents, approximately one-third of adults experienced ANV, while 6% to 11% reported anticipatory vomiting.[1] A study of children in the pre–5-HT3 receptor antagonist era reported anticipatory nausea in 23 (29%) of 80 children and anticipatory vomiting in 16 (20%) of 80 children who had received 11 cycles of antineoplastic therapy, on average, before evaluation.[2] In the post–5-HT3 receptor antagonist era, the reported prevalence of anticipatory nausea in children has ranged from 0% to 59%.[3] Similar to observations in adult patients, the reported prevalence of anticipatory nausea is always higher than that of anticipatory vomiting in children, although one study reported an equivalent prevalence (5 [26%] of 19 patients) for these conditions.[4]

This section focuses on the management of ANV in children aged 1 month to 18 years who are receiving antineoplastic medication. Optimal control of ANV is defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for the prevention or treatment of chemotherapy-induced N&V (CINV), and no nausea-related change in the child’s usual appetite and diet. This level of ANV control is to be achieved during the 24 hours before administration of the first antineoplastic agent of the upcoming planned antineoplastic cycle.

Approaches to Prevent ANV in Children

ANV appears to be a conditioned response to CINV experienced in the acute phase (24 hours after administration of chemotherapy) and delayed phase (more than 24 hours after and within 7 days of administration of chemotherapy).[3] The anxiety and distress attendant to CINV reinforce the conditioned response.[3] It follows, then, that a higher rate of complete control of acute and delayed CINV would result in lower rates of ANV. Adherence to evidence-based recommendations for CINV prevention has been shown to substantially improve complete control of acute CINV.[5]

Optimized control of acute and delayed CINV may help minimize exposure to the negative stimuli required for conditioning to occur. Consensus recommendations call for antiemetic interventions to be based on published guidelines for the prevention of acute CINV in children receiving antineoplastic agents,[6,7] including antineoplastic agent–naïve patients. Once antineoplastic therapy has been initiated, the selection of antiemetic interventions should be informed by evidence-based guidelines and tailored to the patient’s CINV control and any adverse effects associated with antiemetic agents.

Interventions to Control ANV in Children

Hypnosis

Hypnosis has been defined as an intervention that “provides suggestions for changes in sensation, perception, cognition, affect, mood, or behavior.”[8] Two trials evaluated the role of hypnosis in controlling ANV in children. One study recruited 54 children aged 5 to 17 years who had reported experiencing anticipatory nausea, anticipatory vomiting, or both in a previous study and who were about to receive at least two identical antineoplastic treatment courses.[9] On average, children were 15.8 months (range, 0.5–118 months) from their cancer diagnosis at the time of the study. The control group had received antineoplastic therapy for much longer than the other two groups (29.5 months vs. 8 or 11.5 months).

Although it is not possible to precisely ascertain the emetogenicity of the antineoplastic therapy these children received, it appears that most received highly emetogenic treatment. The antiemetic agents taken for prophylaxis were not reported, but children’s antiemetic regimens were unchanged during the trial. The severity of N&V was assessed through semistructured interviews. Children were randomly assigned to receive one of three possible interventions: hypnosis training (imagination-focused therapy), active cognitive distraction (relaxation), or contact with a therapist (control). The authors reported a significant improvement in complete control of anticipatory vomiting in the group who received hypnosis training (12 [57%] of 21 patients at baseline vs. 18 [86%] of 21 patients after hypnosis training; P < .05). Complete control of anticipatory nausea increased from 5 (24%) of 21 patients at baseline to 8 (38%) of 21 patients after hypnosis training.[9]

Another study evaluated hypnosis as a means of preventing ANV in 20 children aged 6 to 18 years who were naïve to chemotherapy.[10] Controls were matched for age (±3 years) and the emetogenicity of their antineoplastic treatment. Insufficient information is available to determine the emetogenicity of the antineoplastic regimens. Children randomly assigned to receive hypnosis did not receive antiemetic prophylaxis but did receive antiemetic agents as needed. Children in the control group received standard antiemetic prophylaxis for 4 to 6 hours after antineoplastic therapy. Ondansetron was given to more children in the control group (7 of 10 patients) than in the hypnosis group (3 of 10 patients).

Children randomly assigned to receive hypnosis were taught self-hypnosis during the initial antineoplastic treatment, while children in the control group spent equivalent time in conversation with a therapist. Researchers used a daily structured interview with the children to assess ANV at 1 to 2 months, and at 4 to 6 months after diagnosis. At the time of first assessment, children who had been taught self-hypnosis reported significantly less anticipatory nausea than did the control group, although the incidence was not reported. The rate of anticipatory vomiting was identical in each group (1 of 10 patients). By the time of the second assessment, there was no difference between the groups in the rate of anticipatory nausea. The rate of anticipatory vomiting between the groups was also similar (hypnosis, 0 of 10 patients vs. control, 2 of 10 patients).[10]

Pharmacological interventions

Studies of pharmacological interventions for ANV have been conducted only in adults and are limited to benzodiazepines. Because patients who experience ANV have been observed to be more anxious than patients who do not experience ANV,[11] anxiolytics have been studied. Studies in adults have evaluated the contribution of benzodiazepines as a treatment for ANV.[12,13] In one randomized trial, adult cancer patients received placebo or lorazepam 2 mg by mouth the night before antineoplastic treatment, the morning of treatment, and at bedtime for the next 5 days during 180 antineoplastic treatment courses containing cisplatin.[12] Patients also received metoclopramide 2 mg/kg per dose, clemastine, and dexamethasone for antiemetic prophylaxis. At the time of randomization, approximately two-thirds of patients were naïve to antineoplastic agents. ANV was defined as nausea, vomiting, or both that occurred within 12 hours before antineoplastic therapy or 1 hour after the start of antineoplastic therapy. A significantly higher proportion of treatments with lorazepam were associated with complete ANV control, compared with the control group (52% vs. 32%; P < .05). Few adverse effects occurred; 76% of the patients who received lorazepam and 32% of the controls had mild sedation.

Women with breast cancer who were naïve to antineoplastic treatment were enrolled in a double-blind placebo-controlled trial comparing the incidence of ANV after relaxation training and either alprazolam (29 patients) or placebo (28 patients). Alprazolam 0.25 mg or placebo was given twice daily by mouth for 6 to 12 months. Triazolam was also given as needed to patients in both study arms to manage insomnia. The proportion of patients who experienced complete control of anticipatory nausea and anticipatory vomiting before the fourth antineoplastic treatment was similar in both study arms (26% vs. 25% and 4% vs. 0%, respectively). Diazepam 5 mg twice daily was given to 29 adult cancer patients with ANV for 3 days before each of four consecutive antineoplastic treatment courses.[13] Thirteen patients (45%) experienced complete ANV control at some time over the four antineoplastic treatment courses.

Conclusions

While the improvement in complete control of ANV provided by psychological interventions such as hypnosis or systematic desensitization may not be dramatic, these interventions may benefit individual patients with minimal risk. For this reason, one guideline development panel recommends that such interventions be offered to age-appropriate patients who experience ANV where the expertise and resources exist to deliver them.[6]

Despite the lack of evidence supporting the use of benzodiazepines to treat ANV in children, guidelines based on clinical experience recommend using lorazepam for ANV in children.[14] The recommended initial dose was based on current pediatric dosing recommendations, with the usual adult dose as the maximum dose.[15] This dose should be titrated to the needs of each child, with dose lowering recommended for excessive sedation.

References
  1. Morrow GR, Roscoe JA, Hynes HE, et al.: Progress in reducing anticipatory nausea and vomiting: a study of community practice. Support Care Cancer 6 (1): 46-50, 1998. [PUBMED Abstract]
  2. Dolgin MJ, Katz ER, McGinty K, et al.: Anticipatory nausea and vomiting in pediatric cancer patients. Pediatrics 75 (3): 547-52, 1985. [PUBMED Abstract]
  3. Tyc VL, Mulhern RK, Bieberich AA: Anticipatory nausea and vomiting in pediatric cancer patients: an analysis of conditioning and coping variables. J Dev Behav Pediatr 18 (1): 27-33, 1997. [PUBMED Abstract]
  4. Stockhorst U, Spennes-Saleh S, Körholz D, et al.: Anticipatory symptoms and anticipatory immune responses in pediatric cancer patients receiving chemotherapy: features of a classically conditioned response? Brain Behav Immun 14 (3): 198-218, 2000. [PUBMED Abstract]
  5. Aapro M, Molassiotis A, Dicato M, et al.: The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 23 (8): 1986-92, 2012. [PUBMED Abstract]
  6. Dupuis LL, Boodhan S, Holdsworth M, et al.: Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60 (7): 1073-82, 2013. [PUBMED Abstract]
  7. Patel P, Robinson PD, Devine KA, et al.: Prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting in pediatric cancer patients and hematopoietic stem cell recipients: Clinical practice guideline update. Pediatr Blood Cancer 68 (5): e28947, 2021. [PUBMED Abstract]
  8. Montgomery GH, Schnur JB, Kravits K: Hypnosis for cancer care: over 200 years young. CA Cancer J Clin 63 (1): 31-44, 2013. [PUBMED Abstract]
  9. Zeltzer LK, Dolgin MJ, LeBaron S, et al.: A randomized, controlled study of behavioral intervention for chemotherapy distress in children with cancer. Pediatrics 88 (1): 34-42, 1991. [PUBMED Abstract]
  10. Jacknow DS, Tschann JM, Link MP, et al.: Hypnosis in the prevention of chemotherapy-related nausea and vomiting in children: a prospective study. J Dev Behav Pediatr 15 (4): 258-64, 1994. [PUBMED Abstract]
  11. Andrykowski MA: The role of anxiety in the development of anticipatory nausea in cancer chemotherapy: a review and synthesis. Psychosom Med 52 (4): 458-75, 1990 Jul-Aug. [PUBMED Abstract]
  12. Malik IA, Khan WA, Qazilbash M, et al.: Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol 18 (2): 170-5, 1995. [PUBMED Abstract]
  13. Razavi D, Delvaux N, Farvacques C, et al.: Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam. J Clin Oncol 11 (7): 1384-90, 1993. [PUBMED Abstract]
  14. van Hoff J, Olszewski D: Lorazepam for the control of chemotherapy-related nausea and vomiting in children. J Pediatr 113 (1 Pt 1): 146-9, 1988. [PUBMED Abstract]
  15. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 2.2022. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed April 12, 2023.

Latest Updates to This Summary (07/20/2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Prevention and Management of Acute or Delayed Nausea and Vomiting

Revised Table 5 to update the doses for haloperidol and droperidol and available route for droperidol.

Added Digges et al. as reference 32.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the prevention and control of treatment-related nausea and vomiting in cancer patients. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Nausea and Vomiting Related to Cancer Treatment are:

  • Alison Palumbo, PharmD, MPH, BCOP (Oregon Health and Science University Hospital)
  • Maria Petzel, RD, CSO, LD, CNSC, FAND (University of TX MD Anderson Cancer Center)
  • Megan Reimann, PharmD, BCOP (Total CME)

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Nausea and Vomiting Related to Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /side-effects/nausea/nausea-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389491]

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Gastrointestinal Complications (PDQ®)–Health Professional Version


Gastrointestinal Complications (PDQ®)–Health Professional Version

Overview

Go to Patient Version

Gastrointestinal complications such as constipation, fecal impaction, bowel obstruction, diarrhea, and radiation enteritis are common problems for patients with cancer. The growth and spread of cancer, as well as its treatment, contribute to these conditions.

This summary reviews the definitions, causes, assessment, and treatment of each of these common gastrointestinal side effects. For information about treatment-related nausea and vomiting, see Nausea and Vomiting Related to Cancer Treatment.

Constipation is the slow movement of feces through the large intestine that results in the passage of dry, hard stool. This condition can result in discomfort or pain.[1] The longer the transit time of stool in the large intestine, the greater the fluid absorption and the drier and harder the stool becomes.

Constipation may be annoying and uncomfortable, but fecal impaction can be life-threatening. Impaction is the accumulation of dry, hardened feces in the rectum or colon. The patient with a fecal impaction may present with circulatory, cardiac, or respiratory symptoms rather than with gastrointestinal symptoms.[2] If the fecal impaction is not recognized, the signs and symptoms may progress and result in death.

In contrast to constipation and impaction, a bowel obstruction is a partial or complete occlusion of the bowel lumen by a process other than fecal impaction. Intestinal obstructions can be classified by the type of obstruction, the obstructing mechanism, and the part of the bowel involved.

Diarrhea can occur throughout cancer care, and the effects can be physically and emotionally devastating. Although less prevalent than constipation, diarrhea remains a significant symptom burden for people with cancer. Specific definitions of diarrhea vary widely. Acute diarrhea is generally considered to be an abnormal increase in stool liquid and the passage of more than three unformed stools during a 24-hour period.[3] Diarrhea is considered chronic when it persists longer than 4 weeks. This condition can have a significant impact on quality of life and, if severe, may even be life-threatening. Furthermore, diarrhea can lead to increased caregiver burden.

Radiation enteritis is a functional disorder of the large and small bowel that occurs during or after a course of radiation therapy to the abdomen, pelvis, or rectum. One report also documented radiation-induced diarrhea in individuals with lung or head and neck cancers who were receiving radiation with or without chemotherapy.[4]

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

References
  1. Larkin PJ, Cherny NI, La Carpia D, et al.: Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Ann Oncol 29 (Suppl 4): iv111-iv125, 2018. [PUBMED Abstract]
  2. Hussain ZH, Whitehead DA, Lacy BE: Fecal impaction. Curr Gastroenterol Rep 16 (9): 404, 2014. [PUBMED Abstract]
  3. Moschen AR, Sammy Y, Marjenberg Z, et al.: The Underestimated and Overlooked Burden of Diarrhea and Constipation in Cancer Patients. Curr Oncol Rep 24 (7): 861-874, 2022. [PUBMED Abstract]
  4. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015. [PUBMED Abstract]

Constipation

Causes of Constipation

Constipation can be a presenting symptom of cancer, or it can occur later as a side effect of a growing tumor or treatment of the tumor. For patients with cancer, other causative factors include the following:[1,2]

  • Medications (e.g., chemotherapy drugs, opioids, antacids, diuretics).
  • Diet (inadequate fluid intake, inadequate intake of dietary fiber, decreased appetite).
  • Prolonged immobility and/or inadequate exercise.
  • Bowel disorders (e.g., inflammatory bowel disease, diverticulitis).
  • Neuromuscular disorders (disruption of innervation leading to atony of the bowel, spinal cord injury or compression).
  • Metabolic disorders (e.g., dehydration, hypercalcemia, hypokalemia, uremia).
  • Depression.
  • Environmental factors (lack of privacy, change in bathroom habits, assistance to get to the bathroom).

Any of these factors can occur because of the disease process, aging, debilitation, or treatment.

Constipation is frequently the result of autonomic neuropathy caused by vinca alkaloids, oxaliplatin, taxanes, and thalidomide. Other drugs, such as opioid analgesics and anticholinergics (including antidepressants and antihistamines), may lead to constipation by causing decreased sensitivity to the defecation reflex and decreased gut motility. Because constipation is common with the use of opioids, a bowel regimen should be initiated when opioids are prescribed and continued for as long as the patient takes them. Opioids produce varying degrees of constipation, suggesting a dose-related phenomenon. One study suggested that clinicians should not prescribe laxatives based on the opioid dose, but rather should titrate the laxative according to bowel function. Lower doses of opioids or weaker opioids, such as codeine, are just as likely to cause constipation as higher doses and stronger opioids.[3] For more information about opioid-induced constipation, see the Constipation section in Cancer Pain.

Assessment of Constipation

A normal bowel pattern is having at least three stools per week and no more than three stools per day; however, these criteria may be inappropriate for patients with cancer.[4,5]

The following questions may provide a useful assessment guide:

  1. What is normal for the patient (frequency, amount, and timing)?
  2. When was the last bowel movement? What was the amount, consistency, and color? Was blood passed with it?
  3. Has the patient been having any abdominal discomfort, cramping, nausea or vomiting, pain, excessive gas, or rectal fullness?
  4. Does the patient regularly use laxatives or enemas? What does the patient usually do to relieve constipation? Does it usually work?
  5. What type of diet does the patient follow? How much and what type of fluids are taken on a regular basis?
  6. What medications (dose and frequency) is the patient taking?
  7. Is this symptom a recent change?
  8. How many times a day is flatus passed?

A thorough history of the patient’s bowel pattern, dietary changes, and medications, along with a physical examination, can identify possible causes of constipation. The evaluation also includes assessment of associated symptoms such as distention, flatus, cramping, or rectal fullness. The following tests may be part of the clinical evaluation:[6]

  • Digital rectal exam: Done to rule out fecal impaction at the level of the rectum.
  • Fecal occult blood test: Helpful in determining a possible intraluminal lesion.
  • Colonoscopy or sigmoidoscopy: Necessary if cancer is suspected.

Physical assessment will determine the presence or absence of bowel sounds, flatus, or abdominal distention. Patients with colostomies are assessed for constipation. Dietary habits, fluid intake, activity levels, and use of opioids in these patients are examined.

Management of Constipation

Comprehensive management of constipation includes prevention (if possible), elimination of causative factors, and judicious use of laxatives. Some patients can be encouraged to increase dietary fiber (fruits; green, leafy vegetables; 100% whole-grain cereals and breads; and bran) and to drink eight 8-oz. (240-mL) glasses of fluid daily unless contraindicated. For more information, see Nutrition in Cancer Care.

Nonpharmacological interventions

The following interventions may be done before or with the use of pharmacological agents:

  • Record bowel movements daily.
  • Encourage patient to increase fluid intake, unless contraindicated.
  • Encourage regular exercise, including abdominal exercises in bed or moving from bed to chair if the patient is not ambulatory.
  • Encourage adequate fiber intake.
  • Provide a warm or hot drink approximately one-half hour before time of patient’s usual defecation.
  • Provide privacy and quiet time at the patient’s usual or planned time for defecation.
  • Provide a toilet or bedside commode and appropriate assistive devices; avoid bedpan use whenever possible.

Contraindications

Rectal agents should be avoided in patients with cancer at risk of thrombocytopenia, leukopenia, and/or mucositis from cancer and its treatment. In immunocompromised patients, manipulation of the rectum and anus should be avoided (i.e., no rectal examinations, no suppositories, and no enemas). These actions can lead to the development of anal fissures or abscesses, which are portals of entry for infection. Also, the stoma of a patient with neutropenia should not be manipulated unnecessarily.

Transanal irrigation is a procedure in which water is introduced into the bowel through the anus. A systematic review suggested that this procedure may be beneficial for patients with neurogenic bowel disease, low anterior resection syndrome, fecal incontinence, and chronic constipation. However, its efficacy is unknown in patients with cancer who have constipation.[7]

Medical agents for constipation

There are different medical agents used to treat constipation. Table 1 lists these agents in more detail.

Table 1. Medical Agents for Constipation
Name Action Caution/Side Effects Onset Selected Drugs/Dosages
GI = gastrointestinal; IBS = irritable bowel syndrome; N/A = not applicable; PO = orally.
Bulk producers Natural or semisynthetic polysaccharide and cellulose that work with the body’s natural processes to hold water in intestinal tract, soften stool, and increase frequency of stool passage. To reduce risk of bowel obstruction, take with two 8-oz. (240-mL) glasses of water and maintain adequate hydration. 12–24 h (may be delayed up to 72 h) Methylcellulose: 2 g dissolved in 8-oz. (240-mL) glass of water PO up to three times daily. Increase as needed by 2 g.
Avoid if fecal impaction or intestinal obstruction is suspected.
Not advised for opioid-induced constipation. Psyllium: 2.5-30 g PO daily in divided doses.
Saline laxatives High osmolarity attracts water into lumen of the intestines. Fluid accumulation alters stool consistency, distends bowel, and induces peristaltic movement. Repeated use can alter fluid and electrolyte balance. 0.5–6 h Magnesium sulfate: 10–20 g dissolved in 8-oz. (240-mL) glass of water orally. May repeat in 4 h. Do not exceed two doses daily.
Magnesium hydroxide:
  – 400 mg/5 mL liquid: 30–60 mL/day once daily at bedtime or divided.
– 800 mg/5 mL liquid: 15–30 mL/day once daily at bedtime or divided.
– 1,200 mg/5 mL liquid: 10–20 mL/day once daily at bedtime or divided.
Avoid magnesium-containing laxatives in patients with renal dysfunction. Avoid sodium-containing laxatives in patients with edema, congestive heart failure, megacolon, or hypertension. Magnesium citrate: 195–300 mL as single dose or divided doses over 24 h.
Used to clear bowels for rectal or bowel examination. Sodium phosphate enemas can cause acute phosphate nephropathy. Cramps may occur. Sodium phosphate: 4.5-oz. enema as single dose.
Stimulant laxatives Increase motor activity of bowels by direct action on smooth muscle of the intestine. Prolonged use causes laxative dependency and loss of normal bowel function. 6–24 h (oral), 0.25-1 h (bisacodyl suppository) Sennosides: 17.2–34.4 mg PO once or twice daily.
Bisacodyl must be excreted in bile to be active and is not effective with biliary obstruction or diversion. Avoid bisacodyl with known or suspected ulcerative lesions of the colon. May cause cramping.
Used to clear bowels for rectal or bowel examination. Avoid taking bisacodyl within 1 h of taking antacids, milk, or cimetidine; causes premature dissolving of enteric coating, which results in gastric or duodenal stimulation. Bisacodyl: 5–15 mg PO once daily or 10-mg suppository once daily.
Lubricant laxatives Lubricate intestinal mucosa and soften stool to help prevent straining in patients for whom straining would be dangerous. Give on empty stomach at bedtime. Mineral oil prevents absorption of oil-soluble vitamins and drugs. 6–8 h (oral), 2-15 min (rectal) Mineral oil (oral):
With older patients, avoid mineral oil due to aspiration potential that can cause lipid pneumonitis.
Can interfere with postoperative healing of anorectal surgery.   – Nonemulsified: 15–45 mL in 24 h.
– Emulsified: 30–90 mL daily as single dose or divided.
Avoid giving with docusate sodium, which causes increased systemic absorption of mineral oil. Mineral oil (rectal): 118 mL as single dose.
Fecal softeners Promote water retention, softening stool to prevent straining; most beneficial when stool is hard. Stool softeners and emollient laxatives are of limited use because of colonic resorption of water from the forming stool. May increase systemic absorption of mineral oil when administered together. Up to 3 d Docusate sodium: 50–240 mg taken with full glass of water.
Docusate calcium: 240 mg daily until bowel movement is normal.
Not used as sole regimen but may be useful in combination with stimulant laxatives. Docusate potassium: 100–300 mg daily until bowel movement is normal; increase daily fluid intake.
Lactulose Synthetic disaccharide that passes to colon undigested. When broken down in colon, it produces lactic acid, formic acid, acetic acid, and carbon dioxide. These products increase osmotic pressure, increasing amount of water held in stool, which softens stool and increases frequency of passage. Excessive amounts may cause diarrhea with electrolyte losses. 24–48 h 10–20 g PO daily; may increase to 40 g daily.
Avoid in patients with acute abdomen, fecal impaction, or bowel obstruction.
Polyethylene glycol and electrolytes Used to clear bowel with minimal water and sodium loss or gain. Contraindicated in patients with bowel obstruction. 24–96 h 17 g dissolved in 4-8 oz. (120–240 mL) of beverage once daily.
Opioid antagonists Restricted ability to cross blood-brain barrier. Give only if other drugs have failed. Contraindicated in patients with bowel obstruction. In a study of patients with advanced, cancer and other diseases, about 50% of patients defecated within 4 h of receiving the injection.[8,9] Naloxone: Oral oxycodone: naloxone combination in ratio of 2:1[10]
Methylnaltrexone: Subcutaneous 0.15 mg/kg daily or every other day to treat opioid-induced constipation.
Naldemedine: 0.2 mg PO daily for 2 wk[11]
Block opioid receptors peripherally in the GI tract to reverse opioid-induced decreases in intestinal motility. Side effects: Dizziness, nausea, abdominal pain, flatulence, diarrhea. No evidence of withdrawal or other central effects of the opioid; pain scores remained unchanged. Naloxegol: 12.5–25 mg PO daily
Lubiprostone Chloride channel activator that acts to increase intestinal fluid secretion and improve fecal transit, bypassing antisecretory effects of opiates. Contraindicated in patients with bowel obstruction. 24–48 h in chronic constipation.[12] 24 µg PO twice daily (8 µg PO twice daily in IBS).
Dyspnea and chest tightness may occur within 30-60 min of first dose and resolve within a few hours. Syncope and hypotension, some requiring hospitalization, may also occur.
Used for chronic idiopathic constipation, IBS with constipation, and opioid-induced constipation. Side effects: Diarrhea, nausea, headache, abdominal pain.
Linaclotide Guanylate cyclase-C agonist that causes increased chloride and bicarbonate secretion into the intestinal lumen, leading to increased intestinal fluid and GI transit. Contraindicated in patients <2 y and in patients with mechanical GI obstruction. N/A 145 µg PO daily (72 µg PO daily for tolerability or 290 µg PO daily in IBS).
May cause severe diarrhea associated with syncope, hypertension, and electrolyte abnormalities.
Used for chronic idiopathic constipation, IBS with constipation. Side effects: Diarrhea, headache, abdominal pain.
Prucalopride Selective 5-HT4 receptor agonist that stimulates peristaltic reflux and increases intestinal secretions and GI motility. Contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, or severe inflammatory conditions of the GI tract. N/A 2 mg PO daily
Used for chronic idiopathic constipation. Side effects: Diarrhea, nausea, headache, abdominal pain.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Lindberg G, Hamid SS, Malfertheiner P, et al.: World Gastroenterology Organisation global guideline: Constipation–a global perspective. J Clin Gastroenterol 45 (6): 483-7, 2011. [PUBMED Abstract]
  2. Davies A, Leach C, Caponero R, et al.: MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 28 (1): 23-33, 2020. [PUBMED Abstract]
  3. Bennett M, Cresswell H: Factors influencing constipation in advanced cancer patients: a prospective study of opioid dose, dantron dose and physical functioning. Palliat Med 17 (5): 418-22, 2003. [PUBMED Abstract]
  4. Portenoy RK: Constipation in the cancer patient: causes and management. Med Clin North Am 71 (2): 303-11, 1987. [PUBMED Abstract]
  5. McShane RE, McLane AM: Constipation. Consensual and empirical validation. Nurs Clin North Am 20 (4): 801-8, 1985. [PUBMED Abstract]
  6. Bruera E, Suarez-Almazor M, Velasco A, et al.: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 9 (8): 515-9, 1994. [PUBMED Abstract]
  7. Mekhael M, Kristensen HØ, Larsen HM, et al.: Transanal Irrigation for Neurogenic Bowel Disease, Low Anterior Resection Syndrome, Faecal Incontinence and Chronic Constipation: A Systematic Review. J Clin Med 10 (4): , 2021. [PUBMED Abstract]
  8. Thomas J, Karver S, Cooney GA, et al.: Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358 (22): 2332-43, 2008. [PUBMED Abstract]
  9. Portenoy RK, Thomas J, Moehl Boatwright ML, et al.: Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage 35 (5): 458-68, 2008. [PUBMED Abstract]
  10. Meissner W, Leyendecker P, Mueller-Lissner S, et al.: A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 13 (1): 56-64, 2009. [PUBMED Abstract]
  11. Katakami N, Harada T, Murata T, et al.: Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer. J Clin Oncol 35 (34): 3859-3866, 2017. [PUBMED Abstract]
  12. Thayalasekeran S, Ali H, Tsai HH: Novel therapies for constipation. World J Gastroenterol 19 (45): 8247-51, 2013. [PUBMED Abstract]

Fecal Impaction

Causes of Fecal Impaction

Constipation, if left untreated, may lead to fecal impaction. The causes of impaction are the same as the causes of constipation.[1] For more information, see the Causes of Constipation section.

Signs and Symptoms of Fecal Impaction

The patient may exhibit symptoms similar to those of constipation or present with symptoms unrelated to the gastrointestinal system. If the fecal impaction presses on the sacral nerves, the patient may experience back pain. If the impaction presses on the ureters, bladder, or urethra, urinary symptoms, such as urinary retention or increased or decreased frequency or urgency of urination, may develop.

When abdominal distention occurs, movement of the diaphragm may be compromised, which can lead to insufficient aeration with subsequent hypoxia and/or left ventricular dysfunction. Hypoxia can, in turn, precipitate angina or tachycardia. If the vasovagal response is stimulated by the pressure of impaction, the patient may become dizzy and hypotensive.

Movement of stool around the impaction may result in diarrhea, which can be explosive. Coughing or activities that increase intra-abdominal pressure may cause leakage of stool. The leakage may be accompanied by nausea, vomiting, abdominal pain, and dehydration and is virtually diagnostic of the condition. The patient with an impaction may present in an acutely confused and disoriented state, with signs of tachycardia, diaphoresis, fever, elevated or low blood pressure, and/or abdominal fullness or rigidity.

Assessment of Fecal Impaction

Assessment of fecal impaction includes the same questions as for the patient with constipation. Additional assessment includes auscultation of bowel sounds to determine if they are present, absent, hyperactive, or hypoactive. The abdomen is inspected for distention and gently palpated for any masses, rigidity, or tenderness. A rectal examination will determine the presence of stool in the rectum or sigmoid colon. An abdominal x-ray (flat and upright) will show loss of haustral markings, gas patterns reflecting gross amounts of stool, and dilatation proximal to the impaction.[2] For more information, see the Assessment of Constipation section.

Treatment of Fecal Impaction

The primary treatment of impaction is to hydrate and soften the stool so that it can be removed or passed. Enemas (oil retention, tap water, or hypertonic phosphate) lubricate the bowel and soften the stool. Caution must be exercised in that fecal impaction can irritate the bowel wall, and excess enemas may perforate the bowel. The patient may need to be digitally disimpacted if the stool is within reach. This is best done after administering an enema to lubricate the bowel.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Davies A, Leach C, Caponero R, et al.: MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 28 (1): 23-33, 2020. [PUBMED Abstract]
  2. Bruera E, Suarez-Almazor M, Velasco A, et al.: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 9 (8): 515-9, 1994. [PUBMED Abstract]

Large or Small Bowel Obstruction

There are four types of bowel obstruction that include the following:

  1. Simple. An obstruction is blocked in one place.
  2. Closed-loop. An obstruction is blocked in two places. This type may develop when the bowel twists around on itself, isolating the looped section of the bowel and obstructing the portion above it.
  3. Strangulated. There is decreased blood flow to the bowel that, if not relieved, will develop into an incarcerated obstruction.
  4. Incarcerated. The bowel becomes necrotic.

Causes of Bowel Obstruction

The obstructing mechanism can be extrinsic or intrinsic.[1]

Extrinsic causes include the following:

  • Inflammation or trauma to the bowel.
  • Neoplasms.
  • Adhesions.
  • Hernias.
  • Volvulus.
  • Compression from outside the intestinal tract.

Intrinsic causes include the following:

  • Paralytic ileus.
  • Mesenteric embolus or thrombus.
  • Tumor infiltration of the mesentery, bowel muscle, or celiac and enteric plexuses.[2]
  • Endometriosis.

Bowel obstructions are more common in the small intestine than in the colon.[3] Bowel obstructions are frequently seen in the ileum. Small bowel obstructions are often caused by adhesions or hernias, while large bowel obstructions are usually caused by carcinomas, volvulus, or diverticulitis. The presentation of obstruction will relate to whether the small or large intestine is involved.

The most common malignancies that cause bowel obstruction are cancers of the colon, stomach, and ovary.[3] Patients who have had abdominal surgery or abdominal radiation are also at higher risk of developing bowel obstruction. Bowel obstructions are most common during advanced stages of disease.

Assessment and Diagnosis of Bowel Obstruction

Possible symptoms of malignant bowel obstruction include abdominal pain, cramps, distention, nausea, vomiting, absence of gas and stool passage, and, rarely, overflow diarrhea.[3] A complete blood cell count, electrolyte panel, and urinalysis are obtained to evaluate fluid and electrolyte imbalance and/or sepsis. An elevated white blood cell count (15,000–20,000/mm3) suggests bowel necrosis.

Traditionally, flat and upright abdominal films have been used for diagnosis. However, x-rays have only modest sensitivity to detect a bowel obstruction and limited ability to detect the exact site, cause, or complications. Contrast computed tomography (CT) delivers enhanced diagnostic precision. A CT of the abdomen and pelvis with intravenous contrast and/or a CT enterography may be used to diagnose patients suspected of having a small bowel obstruction.[4,5]

Treatment of Acute Bowel Obstruction

Careful serial examinations are necessary to manage patients with progressive abdominal symptoms that may be due to acute bowel obstruction. The principles of supportive care in this setting include bowel rest, volume resuscitation, correction of electrolyte imbalances, and transfusion support if necessary. These measures may precede or accompany decompression efforts.

When bowel obstruction is partial, decompression of the distended bowel may be attempted with nasogastric tubes (NGTs) or intestinal tubes. The use of these tubes may reduce edema, relieve fluid and gas accumulation, or decrease the need for multiple stage procedures.[6] However, surgery may be necessary within 24 hours if there is complete, acute obstruction. The use of self-expandable stents to decompress complete, acute malignant bowel obstruction has been noted to decrease the frequency of unnecessary surgery. The stents permit staging of the disease, increase the rate of primary anastomosis relative to colostomy, and decrease morbidity in patients with left-sided colon and rectal malignancies. Further study is warranted, including cost analysis.[7]

Management of Chronic, Malignant Bowel Obstruction

Patients with advanced cancer may have chronic, progressive bowel obstruction that is inoperable.[8,9] The most frequent causes of inoperability are extensive tumor and multiple partial obstructions.[10,11][Level of evidence: II][12] A retrospective review evaluated surgical palliation of malignant bowel obstruction secondary to peritoneal carcinomatosis in 63 patients with nongynecological cancers. The ability to tolerate solid food at hospital discharge was the criterion for successful palliation. Multiple logistic regression analysis identified the absence of ascites and obstruction not involving the small bowel as predictors of successful surgical palliation in this population. Successful palliation was achieved in 45% of patients and was maintained in 76% of this group at a median follow-up of 78 days, for an overall success rate of 35%. The postoperative mortality rate was 15%, and postoperative complications occurred in 44% of patients.[13]

For some patients with malignant obstructions of the gastrointestinal tract, the use of expandable metal stents may provide palliation of obstructive symptoms. Esophageal, biliary, gastroduodenal, and colorectal stents are available.[7,14–19] They may be placed under endoscopic guidance, with or without fluoroscopy, or by an interventional radiologist using fluoroscopy. Morbidity with stent placement may be lower than with surgery. Adequate imaging of the stricture itself and the gastrointestinal tract distal to the stricture is recommended to assess stricture length, detect multifocal disease, and determine the appropriateness of stenting.[20,21][Level of evidence: II][22]

When neither surgery nor stenting is possible, the accumulation of the unabsorbed secretions produce nausea, vomiting, pain, and colicky activity as a result of the partial or complete occlusion of the lumen. In this case, temporary decompression may be accomplished using an NGT; however, NGTs are not favored as a long-term solution.[3] Instead, a gastrostomy tube is commonly used to provide decompression of air and fluid that may accumulate and cause visceral distention and pain. The gastrostomy tube is placed into the stomach and is attached to a drainage bag that can be easily concealed under clothing. When the valve between the gastrostomy tube and the bag is open, the patient may be able to eat or drink by mouth without creating discomfort since the food is drained directly into the bag. Dietary discretion is advised to minimize the risk of tube obstruction by solid food. If the obstruction improves, the valve can be closed, and the patient may once again benefit from enteral nutrition.

Sometimes, decompression is difficult even with a gastrostomy tube in place. Accumulation of fluid may interfere with decompression because several liters of gastrointestinal secretions may be produced per day. Pharmacological symptom management may be necessary. In the case of complete obstruction, avoid oral administration of medications if possible. To relieve continuous abdominal pain, opioid analgesics may be necessary. Associated nausea and vomiting may be treated with several different medications, including scopolamine, octreotide, dexamethasone, haloperidol, metoclopramide, dimenhydrinate, prochlorperazine, serotonin antagonists, and olanzapine.[3] Effective antispasmodics in this situation include anticholinergics (such as scopolamine) [23] and possibly corticosteroids, as well as centrally acting agents.

Careful use of laxatives may be considered for constipation associated with partial bowel obstruction. However, a 2022 systematic review did not identify any studies that examined laxatives in this setting.[3] Osmotic laxatives, such as polyethylene glycol 3350, pull water into the lumen of the bowel, softening stool and increasing peristalsis. Bulk-forming laxatives such as psyllium should be avoided because they increase stool volume and can worsen the obstruction. Finally, manual disimpaction may be necessary if fecal impaction is noted during physical examination.

Another option for management of refractory pain and/or nausea is the synthetic somatostatin analogue octreotide. This agent inhibits the release of several gastrointestinal hormones and reduces gastrointestinal secretions.[24,25][Level of evidence: I][26]

Octreotide is usually given subcutaneously at 50 to 200 µg three times per day and may reduce the nausea, vomiting, and abdominal pain of malignant bowel obstruction. For select patients in whom octreotide alone is ineffective, the addition of an anticholinergic such as scopolamine may help reduce the associated painful colic of malignant bowel obstruction. When either scopolamine or octreotide is used alone, each is ineffective.[14,27–29] Corticosteroids are widely used to treat bowel obstruction, but empirical support is limited.[30]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Rami Reddy SR, Cappell MS: A Systematic Review of the Clinical Presentation, Diagnosis, and Treatment of Small Bowel Obstruction. Curr Gastroenterol Rep 19 (6): 28, 2017. [PUBMED Abstract]
  2. Cousins SE, Tempest E, Feuer DJ: Surgery for the resolution of symptoms in malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev (1): CD002764, 2016. [PUBMED Abstract]
  3. Madariaga A, Lau J, Ghoshal A, et al.: MASCC multidisciplinary evidence-based recommendations for the management of malignant bowel obstruction in advanced cancer. Support Care Cancer 30 (6): 4711-4728, 2022. [PUBMED Abstract]
  4. Lee YC, Jivraj N, O’Brien C, et al.: Malignant Bowel Obstruction in Advanced Gynecologic Cancers: An Updated Review from a Multidisciplinary Perspective. Obstet Gynecol Int 2018: 1867238, 2018. [PUBMED Abstract]
  5. Chang KJ, Marin D, Kim DH, et al.: ACR Appropriateness Criteria® Suspected Small-Bowel Obstruction. J Am Coll Radiol 17 (5S): S305-S314, 2020. [PUBMED Abstract]
  6. Horiuchi A, Maeyama H, Ochi Y, et al.: Usefulness of Dennis Colorectal Tube in endoscopic decompression of acute, malignant colonic obstruction. Gastrointest Endosc 54 (2): 229-32, 2001. [PUBMED Abstract]
  7. Martinez-Santos C, Lobato RF, Fradejas JM, et al.: Self-expandable stent before elective surgery vs. emergency surgery for the treatment of malignant colorectal obstructions: comparison of primary anastomosis and morbidity rates. Dis Colon Rectum 45 (3): 401-6, 2002. [PUBMED Abstract]
  8. Ripamonti C, Bruera E: Palliative management of malignant bowel obstruction. Int J Gynecol Cancer 12 (2): 135-43, 2002 Mar-Apr. [PUBMED Abstract]
  9. Potluri V, Zhukovsky DS: Recent advances in malignant bowel obstruction: an interface of old and new. Curr Pain Headache Rep 7 (4): 270-8, 2003. [PUBMED Abstract]
  10. Jung GS, Song HY, Kang SG, et al.: Malignant gastroduodenal obstructions: treatment by means of a covered expandable metallic stent-initial experience. Radiology 216 (3): 758-63, 2000. [PUBMED Abstract]
  11. Camúñez F, Echenagusia A, Simó G, et al.: Malignant colorectal obstruction treated by means of self-expanding metallic stents: effectiveness before surgery and in palliation. Radiology 216 (2): 492-7, 2000. [PUBMED Abstract]
  12. Coco C, Cogliandolo S, Riccioni ME, et al.: Use of a self-expanding stent in the palliation of rectal cancer recurrences. A report of three cases. Surg Endosc 14 (8): 708-11, 2000. [PUBMED Abstract]
  13. Blair SL, Chu DZ, Schwarz RE: Outcome of palliative operations for malignant bowel obstruction in patients with peritoneal carcinomatosis from nongynecological cancer. Ann Surg Oncol 8 (8): 632-7, 2001. [PUBMED Abstract]
  14. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001. [PUBMED Abstract]
  15. Law WL, Chu KW, Ho JW, et al.: Self-expanding metallic stent in the treatment of colonic obstruction caused by advanced malignancies. Dis Colon Rectum 43 (11): 1522-7, 2000. [PUBMED Abstract]
  16. Repici A, Reggio D, De Angelis C, et al.: Covered metal stents for management of inoperable malignant colorectal strictures. Gastrointest Endosc 52 (6): 735-40, 2000. [PUBMED Abstract]
  17. Harris GJ, Senagore AJ, Lavery IC, et al.: The management of neoplastic colorectal obstruction with colonic endolumenal stenting devices. Am J Surg 181 (6): 499-506, 2001. [PUBMED Abstract]
  18. Aviv RI, Shyamalan G, Watkinson A, et al.: Radiological palliation of malignant colonic obstruction. Clin Radiol 57 (5): 347-51, 2002. [PUBMED Abstract]
  19. Dauphine CE, Tan P, Beart RW, et al.: Placement of self-expanding metal stents for acute malignant large-bowel obstruction: a collective review. Ann Surg Oncol 9 (6): 574-9, 2002. [PUBMED Abstract]
  20. Lopera JE, Alvarez O, Castaño R, et al.: Initial experience with Song’s covered duodenal stent in the treatment of malignant gastroduodenal obstruction. J Vasc Interv Radiol 12 (11): 1297-303, 2001. [PUBMED Abstract]
  21. Razzaq R, Laasch HU, England R, et al.: Expandable metal stents for the palliation of malignant gastroduodenal obstruction. Cardiovasc Intervent Radiol 24 (5): 313-8, 2001 Sep-Oct. [PUBMED Abstract]
  22. Baron TH, Rey JF, Spinelli P: Expandable metal stent placement for malignant colorectal obstruction. Endoscopy 34 (10): 823-30, 2002. [PUBMED Abstract]
  23. De Conno F, Caraceni A, Zecca E, et al.: Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 6 (8): 484-6, 1991. [PUBMED Abstract]
  24. Ripamonti C, Mercadante S, Groff L, et al.: Role of octreotide, scopolamine butylbromide, and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial. J Pain Symptom Manage 19 (1): 23-34, 2000. [PUBMED Abstract]
  25. Mystakidou K, Tsilika E, Kalaidopoulou O, et al.: Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double- blind, controlled clinical trial. Anticancer Res 22 (2B): 1187-92, 2002 Mar-Apr. [PUBMED Abstract]
  26. Fallon MT: The physiology of somatostatin and its synthetic analogue, octreotide. European Journal of Palliative Care 1 (1): 20-2, 1994.
  27. Mercadante S: Assessment and management of mechanical bowel obstruction. In: Portenoy RK, Bruera E, eds.: Topics in Palliative Care. Volume 1. Oxford University Press, 1997, pp. 113-30.
  28. Fainsinger RL: Integrating medical and surgical treatments in gastrointestinal, genitourinary, and biliary obstruction in patients with cancer. Hematol Oncol Clin North Am 10 (1): 173-88, 1996. [PUBMED Abstract]
  29. Ripamonti C, Panzeri C, Groff L, et al.: The role of somatostatin and octreotide in bowel obstruction: pre-clinical and clinical results. Tumori 87 (1): 1-9, 2001 Jan-Feb. [PUBMED Abstract]
  30. Davis M, Hui D, Davies A, et al.: Medical management of malignant bowel obstruction in patients with advanced cancer: 2021 MASCC guideline update. Support Care Cancer 29 (12): 8089-8096, 2021. [PUBMED Abstract]

Diarrhea

The prevalence and severity of diarrhea in patients with cancer vary greatly. Some chemotherapeutic regimens, particularly those containing fluoropyrimidines or irinotecan, are associated with diarrhea rates as high as 50% to 80%.[1] Gastrointestinal toxicity, ranging from diarrhea to severe colitis, is an immune-related adverse effect associated with immune checkpoint inhibitor (ICI) treatment. The rate of diarrhea appears to be dose dependent with anti-CTLA-4 inhibitors and greater with dual checkpoint inhibitor regimens compared with a single agent.[2,3] Rates of any grade diarrhea are 16% to 37% for single-agent PD-L and PD-L1, 32% to 49% for single-agent anti-CTLA-4, and 17% to 44% for dual ICI regimens.[4–6] Diarrhea is also commonly observed in patients with carcinoid tumors who are receiving radiation therapy to abdominal/pelvic fields or undergoing bone marrow transplantation or surgical intervention of the gastrointestinal tract.[7] In a large heterogeneous sample of patients with cancer in various stages of treatment, the prevalence of moderate-to-severe diarrhea was 14%.[8] Among children with cancer during the last month of life, 19% experienced diarrhea.[9]

The consequences of diarrhea can be significant and life-threatening. According to the National Cancer Institute’s (NCI’s) Common Terminology Criteria for Adverse Events, more than half of patients who received chemotherapy for colorectal cancer experienced diarrhea of grade 3 or 4, requiring treatment changes or the reduction, delay, or discontinuation of therapy (see Table 2).[10,11] A review of several clinical trials of irinotecan plus high-dose fluorouracil and leucovorin for colorectal cancer treatment revealed early death rates of 2.2% to 4.8%, primarily due to gastrointestinal toxicity.[12] With the advent of more aggressive anticancer therapies, the potential physical and psychosocial consequences of diarrhea and its indirect effect on cancer treatment outcomes are likely to expand.[13]

Table 2. National Cancer Institute’s Common Terminology Criteria for Adverse Events: Diarrheaa,b
Grade Description
ADL = activities of daily living.
aAdapted from National Cancer Institute.[11]
bDefinition: A disorder characterized by an increase in frequency and/or loose or watery bowel movements.
cInstrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
dSelf-care ADL refers to bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden.
1 Increase of <4 stools/day over baseline; mild increase in ostomy output compared with baseline
2 Increase of 4–6 stools/day over baseline; moderate increase in ostomy output compared with baseline; limiting instrumental ADLc
3 Increase of ≥7 stools/day over baseline; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care ADLd
4 Life-threatening consequences; urgent intervention indicated
5 Death

Causes of Diarrhea

In patients being treated for cancer, diarrhea is most commonly induced by therapy.[14] Conventional methods of diarrhea-causing treatment include the following:

  • Surgery.
  • Chemotherapy.
  • Immunotherapy.
  • Radiation therapy.
  • Bone marrow transplantation.

Other causes of acute diarrhea include the following:[15]

  • Antibiotic therapy.
  • Tube feeding.
  • Stress and anxiety associated with cancer diagnosis and treatment.
  • Infection.

Typical infections are of viral, bacterial, protozoan, parasitic, or fungal etiology. They may also be caused by pseudomembranous colitis, which often does not respond to treatment.[7] Clostridium difficile is a common cause of pseudomembranous colitis.

Other causes of diarrhea in patients with cancer include the underlying cancer, responses to diet, or concomitant diseases (see Table 3). Common causes of diarrhea in patients receiving palliative care are difficulty adjusting the laxative regimen and impaction leading to leakage of stool around the fecal obstruction.

Surgery, a primary treatment modality for many cancers, can affect the body by mechanical, functional, and physiological alterations. Postsurgical complications of gastrointestinal surgery that affect normal bowel function may contribute to diarrhea.[16]

Certain chemotherapeutic agents can alter normal absorption and secretion functions of the small bowel, resulting in treatment-related diarrhea (see Table 3 and Table 5). Patients who are receiving concomitant abdominal or pelvic radiation therapy or recovering from recent gastrointestinal surgery will often experience more severe diarrhea.

Radiation therapy to abdominal, pelvic, lumbar, or para-aortic fields can result in changes to normal bowel function. Factors contributing to the occurrence and severity of intestinal complications include the following:

  • Total dose of radiation.
  • Fractionation of radiation.
  • Volume of bowel irradiated.
  • Concomitant chemotherapy.

Acute intestinal side effects occur at approximately 10 Gy and may last up to 8 to 12 weeks posttherapy. Chronic radiation enteritis may occur months to years after therapy ends. This condition necessitates dietary modification, pharmacological management, and, in some instances, surgical intervention. For more information, see the Radiation Enteritis section.

Graft-versus-host disease (GVHD) is a major complication of allogeneic transplantation. It commonly affects the intestinal tract, skin, and liver. Symptoms of gastrointestinal GVHD include nausea and vomiting, severe abdominal pain and cramping, and watery diarrhea.[17] The volume of accompanying GVHD-associated diarrhea may reach up to several liters per day and is an indicator of the degree and extent of mucosal damage.[17] Acute GVHD is usually manifested within 100 days posttransplant, although it can occur as early as 7 to 10 days posttransplant. It may resolve or develop into a chronic form requiring long-term treatment and dietary management.

Table 3. Possible Contributors to Diarrhea in Patients With Cancer
Cancer [18,19] Carcinoid syndrome
Colon cancer
Lymphoma
Medullary carcinoma of the thyroid
Pancreatic cancer, particularly islet cell tumors (Zollinger-Ellison syndrome)
Pheochromocytoma
Surgery or procedure [20] Celiac plexus block
Cholecystectomy, esophagogastrectomy
Gastrectomy, pancreaticoduodenectomy (Whipple procedure)
Intestinal resection (malabsorption due to short bowel syndrome)
Vagotomy
Chemotherapy See Table 4 for more information.
Radiation therapy (For more information, see the Radiation Enteritis section.) [21] Irradiation to the abdomen, para-aortics, lumbar, and pelvis or radiation for lung and head and neck cancers
Bone marrow transplantation [22] Conditioning chemotherapy, total-body irradiation, graft-versus-host disease after allogeneic bone marrow or peripheral blood stem cell transplants
Drug adverse effects [18,19] Antibiotics, magnesium-containing antacids, antihypertensives, colchicine, digoxin, lactulose, laxatives, methyldopa, metoclopramide, misoprostol, potassium supplements, propranolol, theophylline
Concurrent disease [18,19] Diabetes, hyperthyroidism, inflammatory bowel disease (Crohn disease, diverticulitis, gastroenteritis, HIV/AIDS, ulcerative colitis), obstruction (tumor related)
Infection [23] Clostridium difficile, Clostridium perfringens, Bacillus cereus, Giardia lamblia, Cryptosporidium, Salmonella, Shigella, Campylobacter, Rotavirus
Fecal impaction [18,19] Constipation leading to obstruction
Diet [18,19] Alcohol, milk, dairy products (particularly in patients with lactose intolerance)
Caffeine-containing products (coffee, tea, chocolate); specific fruit juices (prune juice, unfiltered apple juice, sauerkraut juice)
High-fiber foods (raw fruits and vegetables, nuts, seeds, whole-grain products, dried legumes); high-fat foods (deep-fried foods, high fat–containing foods)
Lactulose intolerance or food allergies
Sorbitol-containing foods (candy and chewing gum); hot and spicy foods; gas-forming foods and beverages (cruciferous vegetables, dried legumes, melons, carbonated beverages)
Psychological factors [19] Stress

Some chemotherapeutic agents result in grade 3 or 4 treatment-related diarrhea. Table 4 and Table 5 list the toxicity of intravenous and oral agents used to treat cancer, respectively.

Table 4. Rate of Grade 3 or 4 Diarrhea Associated With Intravenous Chemotherapya
Chemotherapy Agent Grade 3 or 4 Diarrhea Rate (%)b Reference
aIncludes drugs with 5% or greater grade 3 or 4 toxicity.
bHighest percentage listed in current manufacturer prescribing information (single-agent rate of diarrhea listed if provided; excludes irinotecan-based combinations).
Irinotecan 31 [24]
Ziv-aflibercept 19 [24]
Irinotecan, liposomal 13 [24]
Fluorouracil 12.7 [25]
Clofarabine 12 [24]
Pertuzumab 12 [24]
Ipilimumab + nivolumab 11 [24]
Bortezomib 7 [24]
Atezolizumab 6 [24]
Azacitidine 6 [24]
Brentuximab vedotin 6 [24]
Cabazitaxel 6 [24]
Docetaxel 6 [24]
Nab-paclitaxel 6 [24]
Cetuximab 5 [24]
Copanlisib 5 [24]
Elotuzumab 5 [24]
Ipilimumab 5 [24]
Nivolumab 5 [24]
Busulfan 5 [26]
·Table 5. Rate of Grade 3 or 4 Diarrhea Associated With Oral Chemotherapya
Chemotherapy Agent Grade 3 or 4 Diarrhea Rate (%)b Reference
aIncludes drugs with 5% or greater grade 3 or 4 toxicity.
bHighest percentage listed in current manufacturer prescribing information (single-agent rate of diarrhea listed if provided; excludes irinotecan-based combinations).
Selumetinib 24 [24]
Tucatinib (with capecitabine/trastuzumab) 13 [27,28]
Vandetanib 10–11 [29,30]
Umbralisib 10 [31]
Vorinostat 5–8 [32,33]
Sunitinib 4–10 [24]
Sotorasib 4 [34,35]
Selinexor 3–7 [36–38]
Sorafenib 2–8 [39–41]

Assessment of Diarrhea

Rapid yet thorough assessment of diarrhea is imperative because of its potentially life-threatening nature. Few standardized assessment tools are available. As a result, standardized assessment is rare in the clinical setting.[7] For a complete assessment, one author suggests obtaining background information from the patient that includes the type and extent of the patient’s cancer, anticancer treatment, comorbid factors, coexisting symptoms, patient and provider perceptions, and a thorough description of the diarrhea. Stringent monitoring conducted at least weekly is indicated during therapy using chemotherapeutic agents known to cause diarrhea.[12] The NCI’s Common Terminology Criteria for Adverse Events (see Table 2) evaluate diarrhea by the following:[11]

  • Number of stools per day.
  • Incontinence.
  • Increase in ostomy output compared with baseline.
  • Interference with activities of daily living.
  • Hospitalization.

The patient history also includes questions regarding the frequency of bowel movements during the past 24 hours, the character of the fecal material, and the time course of the development of diarrhea.[42] A visual tool to assist patients and families in characterizing the consistency of the stool has been developed.[43] Six diagrams illustrate fecal material consistency ranging from well-formed, formed, and semiformed to loose, very loose, and liquid.

Patients are questioned regarding related symptoms that might indicate hemodynamic compromise or the underlying etiology. Specific questions include information about the following:

  • Dizziness.
  • Orthostatic symptoms.
  • Lethargy.
  • Cramping.
  • Abdominal pain.
  • Nausea.
  • Vomiting.
  • Fever.
  • Rectal bleeding.

These symptoms are classified as complicated or uncomplicated, with therapy based on these classifications.[44]

Uncomplicated diarrhea includes grade 1 or 2 diarrhea with no other signs or symptoms. Management is conservative.

Complicated diarrhea includes grade 1 or 2 diarrhea with any one of the following risk factors:

  • Moderate to severe cramping.
  • Grade 2 or higher nausea/vomiting (see Table 1 in Nausea and Vomiting).
  • Decreased performance status.
  • Fever.
  • Sepsis.
  • Neutropenia.
  • Frank bleeding.
  • Dehydration.

Grade 3 or 4 diarrhea is also classified as complicated. Thorough evaluation and close monitoring is warranted.[44]

The time course of diarrhea and concomitant symptom development are key to determining the underlying etiology.[42] Medication and dietary intake, as well as a history of recent travel, may provide additional clues. Weight loss and reduced urine output provide additional data regarding the severity of the effects of diarrhea.

The goal of physical examination is to identify potential causes of diarrhea and its complications as quickly as possible to reduce morbidity. The physical examination includes vital signs and evaluation of skin turgor and oral mucosa to assess hemodynamic status and dehydration. Abdominal examination includes evaluation for rebound tenderness, guarding, hypoactive or hyperactive bowel sounds, and stool collection. A rectal exam can rule out fecal impaction but is performed judiciously in neutropenic or thrombocytopenic patients.[18]

Laboratory tests may include the following:[18]

  • Stool cultures for bacterial, fungal, and viral pathogens.
  • A complete chemistry panel and hematologic profile. This will provide information regarding the effect of diarrhea on kidney function and electrolytes and identify changes in white blood cell count in response to infection.
  • Urinalysis with specific gravity to provide information regarding hydration status.
  • Stool osmolality may also be measured.

In some cases, radiographic procedures are conducted to identify ileus, obstruction, or other abnormalities. In rare cases, endoscopy may be indicated.

Management of Diarrhea

A review analyzed early toxic deaths in two NCI-sponsored cooperative trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer. It led to the revision of clinical practice guidelines for the treatment of cancer treatment–induced diarrhea, with a heightened emphasis on assessment and early aggressive interventions. The guidelines distinguish between uncomplicated and complicated diarrhea.[44]

Uncomplicated diarrhea

The treatment of cancer-related diarrhea is often empiric and nonspecific. Whenever possible, treat underlying causes such as fecal impaction or modify the stimulant laxative regimen as necessary. Medications such as bulk laxatives and promotility agents (e.g., metoclopramide) are discontinued. Dietary changes are commonly made to stop or lessen the severity of cancer treatment–related diarrhea.[10,22,45] In some cases, these changes include advising patients to eat small, frequent meals and avoid the following:[46]

  • Lactose-containing foods and beverages (milk and dairy products).
  • Spicy foods.
  • Alcohol.
  • Caffeine-containing foods and beverages.
  • Certain fruit juices.
  • Gas-forming foods and beverages.
  • High-fiber foods.
  • High-fat foods.

When experiencing diarrhea, patients are encouraged to increase their intake of clear liquids to at least 3 L per day (e.g., water, sports drinks, broth, weak decaffeinated teas, caffeine-free soft drinks, clear juices, and gelatin).[15,47] For more information, see the Behavioral strategies for symptom management section in Nutrition in Cancer Care.

Some case reports suggest the efficacy of glutamine in relieving diarrhea and other gastrointestinal symptoms associated with cancer therapy. However, a randomized controlled trial that used oral glutamine to prevent pelvic radiation-induced diarrhea did not show any benefit.[48][Level of evidence: I][49,50]

Pharmacological therapy

The goals of pharmacological therapy include inhibition of intestinal motility, reduction in intestinal secretions, and promotion of absorption. Absorbents include agents that form a gelatinous mass that gives density to fecal material. Methylcellulose and pectin are most commonly used, but little data support their efficacy. Some patients may not tolerate these bulk-forming agents because of the large volume required for therapeutic effect and the associated abdominal discomfort and bloating. Adsorbents such as kaolin, clays, and activated charcoals have been used extensively, but no data support their use. Furthermore, they may inhibit absorption of other oral antidiarrheals.

Opioids bind to receptors within the gastrointestinal tract and reduce diarrhea by reducing transit time. Loperamide is the most common opioid used, due to its availability and reduced effect on cognition, although codeine and other opioids can also be effective.[42] Common loperamide doses begin with 4 mg, followed by 2 mg after each unformed stool, with a maximum of approximately 12 mg/day.[18,42] Regardless of the dose, however, loperamide may be less effective in patients with grade 3 or 4 diarrhea.[51][Level of evidence: I]

Mucosal prostaglandin inhibitors, also referred to as antisecretory agents, include the following:

  • Aspirin may be useful for radiation-induced diarrhea.
  • Bismuth subsalicylate is believed to have direct antimicrobial effects on Escherichia coli, so it is used to prevent traveler’s diarrhea. This agent is contraindicated in patients who should not take aspirin, and large doses can produce toxic salicylate levels.
  • Corticosteroids reduce edema associated with bowel obstruction and radiation colitis and can reduce the hormonal influences of some endocrine tumors.
  • Octreotide.

Other pharmacological therapies for the relief of diarrhea may be specific to the underlying mechanism. Delayed diarrhea (>24 hours) occurs with irinotecan. In a small study, six of seven patients obtained relief with oral neomycin (1,000 mg three times daily). This relief occurred without reduction in the active metabolite of irinotecan, SN-38. Thus, the poorly metabolized antibiotic did not alter the efficacy of the chemotherapeutic agent.[52][Level of evidence: II] In another small study, 37 patients with non-small cell lung cancer received irinotecan. Investigators alkalized the patients’ feces through oral administration of sodium bicarbonate, basic water, and ursodeoxycholic acid, while speeding transit time of the drug metabolites (thought to reduce damage to the intestinal lumen by reducing stasis of the drug) using magnesium oxide. The incidence of delayed diarrhea was significantly reduced in this group when compared with 32 patients who received the same chemotherapeutic regimen without oral alkalization and controlled defecation.[53][Level of evidence: III]

In addition to antidiarrheal agents and immunosuppressive medications, a specialized, five-phase dietary regimen may be started to effectively manage diarrhea associated with GVHD:[22]

  1. Phase 1 consists of total bowel rest until diarrhea is reduced. Nitrogen losses associated with diarrhea can be severe and are compounded by the high-dose corticosteroids used to treat GVHD.
  2. Phase 2 reintroduces oral feedings consisting of beverages that are isotonic, low residue, and lactose free to compensate for the loss of intestinal enzymes secondary to alterations in the intestinal villi and mucosa.
  3. If the beverages in phase 2 are well tolerated, phase 3 may reintroduce solids containing minimal lactose, low fiber, low fat, low total acidity, and no gastric irritants.
  4. In phase 4, dietary restrictions are progressively reduced as foods are gradually reintroduced and tolerance is established.
  5. Phase 5 includes resumption of the patient’s regular diet; however, most patients usually remain lactose intolerant.
Probiotics

Probiotics are nutritional supplements that contain a defined amount of viable microorganisms and, upon administration, confer a benefit to the patient.[54] The use of probiotic functional foods (beneficial live microorganisms) to modify gut microflora has been suggested in clinical conditions associated with diarrhea, gut-barrier dysfunction, and inflammatory response.[55] There are a vast number of different strains of probiotics; however, much of the clinical research has investigated species belonging to the families of Lactobacillus and Bifidobacterium. Probiotics have been promoted for the following:[56–62][Level of evidence: I]

  • Prevention of antibiotic-induced diarrhea and rotavirus.
  • Treatment or prevention of inflammatory bowel disease, irritable bowel syndrome, and gastroenteritis.
  • Treatment of necrotizing enterocolitis in premature infants.

In a double-blind, randomized, controlled trial, 450 adults with cancer who were receiving radiation to the pelvic region were randomly assigned to receive the blend probiotic product VSL #3 or placebo during radiation therapy. The authors reported a decrease in the incidence and severity of diarrhea. No adverse events were reported.[63]

Complicated diarrhea

Patients with complicated diarrhea may require further evaluation and more aggressive management. When patients are receiving chemotherapy, additional evaluation includes stool testing (including blood, fecal leukocytes, C. difficile, Salmonella, E. coli, Campylobacter, and infectious colitis), complete blood count, and electrolyte profile.[44] This workup and treatment is also considered for patients who progress to grade 3 or 4 diarrhea while taking loperamide.

The patient’s symptoms will determine the level of care and type of treatments. A panel of experts suggested that severe radiation therapy–induced diarrhea may not require hospitalization. An alternative outpatient unit or intensive home care nursing may be able to provide the same level of care and monitoring.[44] The same panel recommended intravenous fluids, subcutaneous octreotide, and antibiotics for complicated diarrhea. While the optimal dose of octreotide has not been determined, octreotide may be started at a dose of 100 to 150 μg subcutaneously (SC) three times a day or 25 to 50 μg/hour intravenously (IV) with a dose escalation to 500 μg three times a day. This regimen continues until the patient has been diarrhea free for 24 hours.[44]

Octreotide, a somatostatin analogue, is currently the most promising agent in the management of severe diarrhea caused by a variety of diseases and treatments. The doses used in clinical trials have varied widely, and there is no consensus regarding optimal dose. Nevertheless, octreotide has been shown to be effective in relieving diarrhea associated with AIDS, carcinoid syndrome, and vasoactive intestinal polypeptide tumors.[64][Level of evidence: II][19]

Several open-label and randomized controlled studies of octreotide for chemotherapy-induced diarrhea have demonstrated the efficacy of this therapy.[65–67][Level of evidence: I];[68–70][Level of evidence: II] In a prospective trial of 32 patients who had chemotherapy-induced diarrhea that was refractory to loperamide, octreotide 100 µg SC three times a day produced complete resolution in 30 patients. Resolution occurred rapidly, with 5 patients responding within 24 hours after beginning treatment, 14 patients responding within 48 hours, and 11 patients responding within 72 hours. No adverse effects were noted.[71] Octreotide has also been shown to be effective for treating diarrhea associated with GVHD.[72,73]

An expert panel recommended using high-dose loperamide (2 mg q2h) for the first day of chemotherapy-induced, low-grade diarrhea (grade 1 or 2), followed by octreotide (100 µg–150 µg q8h).[42] If the patient presents with severe diarrhea (grade 3 or 4), octreotide (500 μg–1,500 µg SC or IV q8h) may be given as first-line therapy. A phase III, double-blind study of depot octreotide for the prevention of diarrhea during pelvic radiation treatment did not show any benefit.[74] In fact, some gastrointestinal symptoms, such as cramping, may have been worse. Parenteral hydration and electrolyte supplementation may be indicated, and in severe cases, total parenteral nutrition may be initiated. For more information, see Nutrition in Cancer Care.

Unique scenarios

Irinotecan

Irinotecan is notorious for causing diarrhea. Irinotecan is associated with both acute diarrhea (occurring immediately after drug administration) and delayed diarrhea (occurring more than 24 hours after drug administration). Acute diarrhea is related to acute cholinergic excess and responds well to atropine. Delayed diarrhea, however, is typically managed with antidiarrheals and other supportive measures, as outlined above.[1]

Immune checkpoint inhibitors

Immune-mediated colitis is a potential side effect of ICIs. CTLA-4 inhibitors typically cause diarrhea and colitis more frequently than PD-1 and PD-L1 inhibitors, with the highest rates of colitis seen in patients receiving a combination of ICIs.[75] The onset of these events can be unpredictable, but they typically occur within the first ten doses of an ICI and may occur after cessation of an ICI.[76] Symptoms are treated according to the grade of diarrhea/colitis. Patients with mild diarrhea/colitis may be managed symptomatically with fluids and antidiarrheals. More severe diarrhea/colitis may necessitate treatment with systemic steroids and even permanent discontinuation of ICI therapy. Detailed management of ICI-induced diarrhea is further outlined in National Comprehensive Cancer Network guidelines for the management of immunotherapy-related toxicities.[77]

Phosphatidylinositol 3-kinase (PI3K) inhibitors

The U.S. Food and Drug Administration has approved four PI3K inhibitors, two of which (idelalisib and duvelisib) carry a boxed warning for gastrointestinal complications, including diarrhea.[78,79] Given the severity of diarrhea that may be seen with idelalisib, an expert panel convened to develop management strategies for idelalisib-associated diarrhea.[80] Panelists commented that it is not clear whether diarrhea is a class effect of PI3K inhibitors. The authors noted that for idelalisib, two types of diarrhea may be seen. The first type appears to be self-limiting, occurring within the first 8 weeks of treatment. The second type tends to respond poorly to antidiarrheal therapy and occurs later, approximately 7 months after the start of treatment. In the second type of diarrhea, the histological appearance of the colon is consistent with lymphocytic colitis. In this case, the panel recommended considering treatment with steroids or budesonide.[80]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  20. Yahanda AM: Hepatobiliary cancers. In: Berger DH, Feig BW, Fuhrman GM, eds.: The M.D. Anderson Surgical Oncology Handbook. Little, Brown, 1995, pp 194-224.
  21. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015. [PUBMED Abstract]
  22. Charuhas PM: Medical nutrition therapy in bone marrow transplantation. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000, pp 90-8.
  23. DuPont HL: Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 92 (11): 1962-75, 1997. [PUBMED Abstract]
  24. Lexicomp Online. Hudson, Ohio: Lexi-Comp, Inc., 2021. Available online with subscription. Last accessed Feb. 9, 2024.
  25. Iacovelli R, Pietrantonio F, Palazzo A, et al.: Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-fluorouracil: a meta-analysis of published trials. Br J Clin Pharmacol 78 (6): 1228-37, 2014. [PUBMED Abstract]
  26. NDA 20-954 Busulfex (busulfan) Injection. Minnetonka, Minn.: Orphan Medical, Inc., 1999. Available online. Last accessed Aug. 24, 2023.
  27. Murthy RK, Loi S, Okines A, et al.: Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med 382 (7): 597-609, 2020. [PUBMED Abstract]
  28. Curigliano G, Mueller V, Borges V, et al.: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol 33 (3): 321-329, 2022. [PUBMED Abstract]
  29. Leboulleux S, Bastholt L, Krause T, et al.: Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 13 (9): 897-905, 2012. [PUBMED Abstract]
  30. Wells SA, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [PUBMED Abstract]
  31. Fowler NH, Samaniego F, Jurczak W, et al.: Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 39 (15): 1609-1618, 2021. [PUBMED Abstract]
  32. Kim YH, Bagot M, Pinter-Brown L, et al.: Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol 19 (9): 1192-1204, 2018. [PUBMED Abstract]
  33. Schmitt T, Mayer-Steinacker R, Mayer F, et al.: Vorinostat in refractory soft tissue sarcomas – Results of a multi-centre phase II trial of the German Soft Tissue Sarcoma and Bone Tumour Working Group (AIO). Eur J Cancer 64: 74-82, 2016. [PUBMED Abstract]
  34. Hong DS, Fakih MG, Strickler JH, et al.: KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 383 (13): 1207-1217, 2020. [PUBMED Abstract]
  35. Skoulidis F, Li BT, Dy GK, et al.: Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med 384 (25): 2371-2381, 2021. [PUBMED Abstract]
  36. Gounder MM, Razak AA, Somaiah N, et al.: Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Oncol 40 (22): 2479-2490, 2022. [PUBMED Abstract]
  37. Kalakonda N, Maerevoet M, Cavallo F, et al.: Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 7 (7): e511-e522, 2020. [PUBMED Abstract]
  38. Chari A, Vogl DT, Gavriatopoulou M, et al.: Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med 381 (8): 727-738, 2019. [PUBMED Abstract]
  39. Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356 (2): 125-34, 2007. [PUBMED Abstract]
  40. Eisen T, Frangou E, Oza B, et al.: Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. J Clin Oncol 38 (34): 4064-4075, 2020. [PUBMED Abstract]
  41. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]
  42. Kornblau S, Benson AB, Catalano R, et al.: Management of cancer treatment-related diarrhea. Issues and therapeutic strategies. J Pain Symptom Manage 19 (2): 118-29, 2000. [PUBMED Abstract]
  43. Mertz HR, Beck CK, Dixon W, et al.: Validation of a new measure of diarrhea. Dig Dis Sci 40 (9): 1873-82, 1995. [PUBMED Abstract]
  44. Benson AB, Ajani JA, Catalano RB, et al.: Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22 (14): 2918-26, 2004. [PUBMED Abstract]
  45. Polisena CG: Nutrition concerns with the radiation therapy patient. In: McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000, pp 70-8.
  46. McCallum PD, Polisena CG, eds.: The Clinical Guide to Oncology Nutrition. The American Dietetic Association, 2000.
  47. Hogan CM: The nurse’s role in diarrhea management. Oncol Nurs Forum 25 (5): 879-86, 1998. [PUBMED Abstract]
  48. Kozelsky TF, Meyers GE, Sloan JA, et al.: Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol 21 (9): 1669-74, 2003. [PUBMED Abstract]
  49. Savy GK: Glutamine supplementation. Heal the gut, help the patient. J Infus Nurs 25 (1): 65-9, 2002 Jan-Feb. [PUBMED Abstract]
  50. Ziegler TR, Bye RL, Persinger RL, et al.: Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 315 (1): 4-10, 1998. [PUBMED Abstract]
  51. Cascinu S, Bichisao E, Amadori D, et al.: High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients. Support Care Cancer 8 (1): 65-7, 2000. [PUBMED Abstract]
  52. Kehrer DF, Sparreboom A, Verweij J, et al.: Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7 (5): 1136-41, 2001. [PUBMED Abstract]
  53. Takeda Y, Kobayashi K, Akiyama Y, et al.: Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer 92 (2): 269-75, 2001. [PUBMED Abstract]
  54. de Vrese M, Schrezenmeir J: Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol 111: 1-66, 2008. [PUBMED Abstract]
  55. Isolauri E: Probiotics in human disease. Am J Clin Nutr 73 (6): 1142S-1146S, 2001. [PUBMED Abstract]
  56. Johnston BC, Supina AL, Ospina M, et al.: Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev (2): CD004827, 2007. [PUBMED Abstract]
  57. Pillai A, Nelson R: Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev (1): CD004611, 2008. [PUBMED Abstract]
  58. Huertas-Ceballos A, Logan S, Bennett C, et al.: Dietary interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database Syst Rev (1): CD003019, 2008. [PUBMED Abstract]
  59. Alfaleh K, Bassler D: Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev (1): CD005496, 2008. [PUBMED Abstract]
  60. Karimi O, Peña AS: Indications and challenges of probiotics, prebiotics, and synbiotics in the management of arthralgias and spondyloarthropathies in inflammatory bowel disease. J Clin Gastroenterol 42 (Suppl 3 Pt 1): S136-41, 2008. [PUBMED Abstract]
  61. Butterworth AD, Thomas AG, Akobeng AK: Probiotics for induction of remission in Crohn’s disease. Cochrane Database Syst Rev (3): CD006634, 2008. [PUBMED Abstract]
  62. Eghbali A, Ghaffari K, Khalilpour A, et al.: The effects of LactoCare synbiotic administration on chemotherapy-induced nausea, vomiting, diarrhea, and constipation in children with ALL: A double-blind randomized clinical trial. Pediatr Blood Cancer 70 (6): e30328, 2023. [PUBMED Abstract]
  63. Delia P, Sansotta G, Donato V, et al.: Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 13 (6): 912-5, 2007. [PUBMED Abstract]
  64. Cello JP, Grendell JH, Basuk P, et al.: Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial. Ann Intern Med 115 (9): 705-10, 1991. [PUBMED Abstract]
  65. Cascinu S, Fedeli A, Fedeli SL, et al.: Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial. J Clin Oncol 11 (1): 148-51, 1993. [PUBMED Abstract]
  66. Cascinu S, Fedeli A, Fedeli SL, et al.: Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin. Oncology 51 (1): 70-3, 1994 Jan-Feb. [PUBMED Abstract]
  67. Gebbia V, Carreca I, Testa A, et al.: Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy. Anticancer Drugs 4 (4): 443-5, 1993. [PUBMED Abstract]
  68. Petrelli NJ, Rodriguez-Bigas M, Rustum Y, et al.: Bowel rest, intravenous hydration, and continuous high-dose infusion of octreotide acetate for the treatment of chemotherapy-induced diarrhea in patients with colorectal carcinoma. Cancer 72 (5): 1543-6, 1993. [PUBMED Abstract]
  69. Wadler S, Haynes H, Wiernik PH: Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea. J Clin Oncol 13 (1): 222-6, 1995. [PUBMED Abstract]
  70. Cascinu S, Fedeli A, Fedeli SL, et al.: Control of chemotherapy-induced diarrhoea with octreotide in patients receiving 5-fluorouracil. Eur J Cancer 28 (2-3): 482-3, 1992. [PUBMED Abstract]
  71. Zidan J, Haim N, Beny A, et al.: Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 12 (2): 227-9, 2001. [PUBMED Abstract]
  72. Ippoliti C, Champlin R, Bugazia N, et al.: Use of octreotide in the symptomatic management of diarrhea induced by graft-versus-host disease in patients with hematologic malignancies. J Clin Oncol 15 (11): 3350-4, 1997. [PUBMED Abstract]
  73. Morton AJ, Durrant ST: Efficacy of octreotide in controlling refractory diarrhea following bone marrow transplantation. Clin Transplant 9 (3 Pt 1): 205-8, 1995. [PUBMED Abstract]
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Radiation Enteritis

Causes of Radiation Enteritis

Almost all patients undergoing radiation to the abdomen, pelvis, or rectum will show signs of acute enteritis. Injuries are clinically evident during or within 3 months after irradiation, with the greatest prevalence during the fourth and fifth weeks.[1] Chronic radiation enteritis may present months to years after the completion of therapy, or it may begin as acute enteritis and persist after treatment ends. Only 10% to 20% of people treated with radiation to the abdomen develop chronic problems.[2]

The large and small bowel are sensitive to ionizing radiation. Although the probability of tumor control increases with the radiation dose, so does the damage to normal tissues. Acute side effects to the intestines occur with an exposure of approximately 10 Gy. Because curative radiation doses for many abdominal or pelvic tumors range between 25 and 76 Gy, enteritis is likely to occur.[2]

Factors that influence the occurrence and severity of radiation enteritis include the following:[2]

  • Dose and fractionation of radiation.
  • Modality of radiation.
  • Tumor size and extent.
  • Volume of normal bowel treated.
  • Concomitant chemotherapy.
  • Individual patient variables (e.g., previous abdominal or pelvic surgery, hypertension, diabetes mellitus, smoking, inadequate nutrition).

In general, the higher the daily and total dose delivered to the normal bowel and the greater the volume of normal bowel treated, the greater the risk of radiation enteritis. In addition, the individual patient variables listed above can decrease vascular flow to the bowel wall and impair bowel motility, increasing the chance of radiation injury.

Acute Radiation Enteritis

Diagnosis of acute radiation enteritis

Radiation therapy exerts a cytotoxic effect mainly on rapidly proliferating epithelial cells, like those lining the large and small bowel. Crypt cell wall necrosis can be observed 12 to 24 hours after a daily dose of 1.5 to 3 Gy.[3] Progressive loss of cells, villous atrophy, and cystic crypt dilation occur in the ensuing days and weeks. Patients suffering from acute enteritis may complain of nausea, vomiting, abdominal cramping, tenesmus, and watery diarrhea.[1,2] With diarrhea, the digestive and absorptive functions of the gastrointestinal tract are altered or lost, resulting in malabsorption of fat, lactose, bile salts, and vitamin B12. Symptoms of proctitis—including mucoid rectal discharge, rectal pain, and rectal bleeding (if mucosal ulceration is present)—may result from radiation damage to the anus or rectum.

One study of radiation for lung and head and neck cancers, with or without chemotherapy, noted significant diarrhea despite no direct radiation to the large or small intestine. Higher rates were noted for chemoradiation (42%) than for radiation alone (29%). Additionally, this radiation-induced diarrhea was associated with worse health outcomes and increased resource utilization. Individuals with moderate or severe diarrhea were more likely to have a gastrostomy tube placement, weight loss, unplanned office visits, more inpatient days, and longer radiation breaks. This early report requires additional validation studies to fully evaluate the prevalence and impact of this phenomenon.[4]

Acute enteritis occurs during or within 3 months after irradiation, with the greatest prevalence during the fourth and fifth weeks. Acute enteritis symptoms usually resolve 2 to 3 weeks after the completion of treatment, and the mucosa may appear nearly normal.[1]

Management of acute radiation enteritis

Medical management includes treating diarrhea, dehydration, malabsorption, and abdominal or rectal discomfort. Symptoms usually resolve with medications, dietary changes, and rest. If symptoms become severe despite these measures, a treatment break may be warranted.

Medications may include the following:[1,5]

  • Loperamide hydrochloride, a synthetic antidiarrheal agent. Recommended initial dose: Two capsules (4 mg) by mouth every 4 hours, followed by one capsule (2 mg) by mouth after each unformed stool. Daily total dose should not exceed 16 mg (eight capsules).
  • Cholestyramine, a bile salt sequestering agent. Dose: One package by mouth after each meal and at bedtime.
  • Antibiotics.
  • Pentoxifylline.
  • Tocopherol.
  • Steroids.
  • Probiotics.

The role of nutrition

Damage to the intestinal villi from radiation therapy results in a reduction or loss of enzymes, such as lactase. Lactase is essential in the digestion of milk and milk products. Although there is no evidence that a lactose-restricted diet will prevent radiation enteritis, a diet that is lactose free, low fat, and low residue can help manage symptoms.[6][Level of evidence: I]

Foods to avoid

  • Milk and milk products. Exceptions are buttermilk and yogurt, which are often tolerated because lactose is altered by the presence of Lactobacillus. Processed cheese may also be tolerated because the lactose is removed with the whey when it is separated from the cheese curd. Milkshake supplements such as Ensure are lactose free and may be used.
  • Whole-bran bread and cereal.
  • Nuts, seeds, and coconuts.
  • Fried, greasy, or fatty foods.
  • Fresh and dried fruit and some fruit juices such as prune juice.
  • Raw vegetables.
  • Rich pastries.
  • Popcorn, potato chips, and pretzels.
  • Strong spices and herbs.
  • Chocolate, coffee, tea, and soft drinks with caffeine.
  • Alcohol and tobacco.

Foods to encourage

  • Fish, poultry, and meat that are cooked, broiled, or roasted.
  • Bananas, applesauce, peeled apples, and apple and grape juices.
  • White bread and toast.
  • Macaroni and noodles.
  • Baked, boiled, or mashed potatoes.
  • Cooked vegetables that are mild, such as asparagus tips, green and waxed beans, carrots, spinach, and squash.
  • Mild processed cheese, eggs, smooth peanut butter, buttermilk, and yogurt.

Helpful hints

  • Ingest food at room temperature.[7]
  • Drink 3,000 cc of fluid per day. Allow carbonated beverages to lose carbonation before being ingested.
  • Add nutmeg to food, which helps decrease mobility of the gastrointestinal tract.
  • Start a low-residue diet on day 1 of radiation therapy treatment.[Level of evidence: IV]

Chronic Radiation Enteritis

Diagnosis of chronic radiation enteritis

Only 10% to 20% of patients who receive abdominal or pelvic irradiation develop chronic radiation enteritis. Signs and symptoms include the following:[2]

  • Colicky abdominal pain.
  • Bloody diarrhea.
  • Steatorrhea.
  • Weight loss.
  • Nausea and vomiting.

Less common symptoms are bowel obstruction, fistulas, bowel perforation, and massive rectal bleeding.

The initial signs and symptoms occur 6 to 18 months after radiation therapy. Radiological findings include submucosal thickening, single or multiple stenoses, adhesions, and sinus or fistula formation.[8] Microscopic findings include villi that are fibrotic or may be lost altogether. Ulceration is common, varying from simple loss of epithelial layers to ulcers that may penetrate to different depths of the intestinal wall, even to the serosa. Lymphatic tissue is often atrophic or absent. The submucosa is severely diseased. Arterioles and small arteries show profound changes, with hyalinization of the entire wall thickness. The muscularis is often distorted or focally replaced by fibrosis.

The diagnosis of chronic radiation enteritis may be difficult to make. Clinically and radiologically recurrent tumor needs to be ruled out. Because of the possible latency of the illness, it is essential to obtain a detailed history of the patient’s radiation therapy course. It is often advisable to include the radiation therapy physician in managing the patient’s care.

Treatment of chronic radiation enteritis

Medical management of the patient’s symptoms (which are similar to symptoms of acute radiation enteritis) is indicated, with surgical management reserved for severe damage.[6][Level of evidence: I]

The timing and choice of surgical techniques remain somewhat controversial. A lower operative mortality rate (21% vs. 10%) and incidence of anatomic dehiscence (36% vs. 6%) have been reported with intestinal bypass compared with resection.[9][Level of evidence: II][10] Clinicians who favor resection point out that the removal of diseased bowel decreases the mortality rate for resection and is comparable to the bypass procedure.[9] All agree that simple lysis of adhesions is inadequate and that fistulas require bypass.

Surgery is undertaken only after careful assessment of the patient’s clinical condition and extent of radiation damage. Wound healing is often delayed, necessitating prolonged parenteral feeding after surgery. Even after apparently successful operations, symptoms may persist in a significant share of patients.[11]

Prevention of chronic radiation enteritis

Treatment techniques that can minimize the risk of severe radiation enteritis include the following:

  1. Radiation therapy techniques:
    1. Use of a three- or four-field technique (as opposed to a two-field technique) to minimize the amount of small bowel exposed to treatment.
    2. Treatment of the patient in a physical position that will aid in removing as much small bowel from the treatment field as possible (e.g., treating a patient with a full bladder each day to aid in pushing the small bowel up and out of the pelvis when pelvic radiation is given).
    3. Daily treatment of all fields, resulting in a lower integral dose and more homogenous dose distribution.
    4. Use of computerized radiation dosimetry to best design the treatment plan and use of high-energy treatment machines such as linear accelerators that deliver a high dose-to-tumor volume while sparing normal structures.[12]
  2. Surgery. Placing clips in high-risk areas to better define the location or former location of the tumor and aid in radiation treatment planning.
  3. Modification of treatment sequencing. An area for exploration is the sequencing of radiation, chemotherapy, and surgery and its influence on the severity of enteritis.
References
  1. Harb AH, Abou Fadel C, Sharara AI: Radiation enteritis. Curr Gastroenterol Rep 16 (5): 383, 2014. [PUBMED Abstract]
  2. Loge L, Florescu C, Alves A, et al.: Radiation enteritis: Diagnostic and therapeutic issues. J Visc Surg 157 (6): 475-485, 2020. [PUBMED Abstract]
  3. Gusev IA, Guskova AK, Mettler FA: Medical Management of Radiation Accidents. 2nd ed. CRC Press/Taylor & Francis Group, 2001. Also available online. Last accessed May 6, 2023.
  4. Sonis S, Elting L, Keefe D, et al.: Unanticipated frequency and consequences of regimen-related diarrhea in patients being treated with radiation or chemoradiation regimens for cancers of the head and neck or lung. Support Care Cancer 23 (2): 433-9, 2015. [PUBMED Abstract]
  5. Hille A, Christiansen H, Pradier O, et al.: Effect of pentoxifylline and tocopherol on radiation proctitis/enteritis. Strahlenther Onkol 181 (9): 606-14, 2005. [PUBMED Abstract]
  6. Stryker JA, Bartholomew M: Failure of lactose-restricted diets to prevent radiation-induced diarrhea in patients undergoing whole pelvis irradiation. Int J Radiat Oncol Biol Phys 12 (5): 789-92, 1986. [PUBMED Abstract]
  7. Yasko JM: Care of the Client Receiving External Radiation Therapy. Reston Publishing Company, Inc., 1982.
  8. Mendelson RM, Nolan DJ: The radiological features of chronic radiation enteritis. Clin Radiol 36 (2): 141-8, 1985. [PUBMED Abstract]
  9. Lillemoe KD, Brigham RA, Harmon JW, et al.: Surgical management of small-bowel radiation enteritis. Arch Surg 118 (8): 905-7, 1983. [PUBMED Abstract]
  10. Wobbes T, Verschueren RC, Lubbers EJ, et al.: Surgical aspects of radiation enteritis of the small bowel. Dis Colon Rectum 27 (2): 89-92, 1984. [PUBMED Abstract]
  11. Wellwood JM, Jackson BT: The intestinal complications of radiotherapy. Br J Surg 60 (10): 814-8, 1973. [PUBMED Abstract]
  12. Minsky BD, Cohen AM: Minimizing the toxicity of pelvic radiation therapy in rectal cancer. Oncology (Huntingt) 2 (8): 21-5, 28-9, 1988. [PUBMED Abstract]

Latest Updates to This Summary (08/24/2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Diarrhea

Added Eghbali et al. as reference 62.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of gastrointestinal complications, including constipation, impaction, bowel obstruction, diarrhea, and radiation enteritis. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Gastrointestinal Complications are:

  • Alison Palumbo, PharmD, MPH, BCOP (Oregon Health and Science University Hospital)
  • Maria Petzel, RD, CSO, LD, CNSC, FAND (University of TX MD Anderson Cancer Center)
  • Megan Reimann, PharmD, BCOP (Total CME)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Gastrointestinal Complications. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /side-effects/constipation/GI-complications-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389211]

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Gastrointestinal Complications (PDQ®)–Patient Version


Gastrointestinal Complications (PDQ®)–Patient Version

General Information

Go to Health Professional Version

The gastrointestinal (GI) tract is part of the digestive system, which processes nutrients in foods that are eaten and helps pass waste material out of the body. The GI tract includes the stomach and intestines (bowels).

EnlargeGastrointestinal (digestive) system anatomy; drawing shows the esophagus, liver, stomach, small intestine, and large intestine.
The esophagus and stomach are part of the upper gastrointestinal (digestive) system.
  • Food moves from the throat to the stomach through a tube called the esophagus.
  • After food enters the stomach, it is broken down by stomach muscles that mix the food and liquid with digestive juices.
  • After leaving the stomach, partly digested food passes into the small intestine and then into the large intestine.
  • The end of the large intestine, called the rectum, stores the waste from the digested food until it is pushed out of the anus during a bowel movement.
EnlargeGastrointestinal (digestive) system anatomy; drawing shows the esophagus, liver, stomach, colon, small intestine, rectum, and anus.
Anatomy of the lower gastrointestinal (digestive) system showing the colon, rectum, and anus. Other organs that make up the digestive system are also shown.

GI complications refer to a range of problems that can affect the digestive system. GI complications are common in people with cancer and may be caused by the cancer itself, or it can be an effect of cancer treatment or the medicines used to manage symptoms.

Children and adults with cancer may experience similar types of GI complications, but the causes and treatment approaches differ based on age and other factors. This page describes the following GI complications in adults, their causes, and treatments:

Constipation

Key Points

  • Constipation is a condition in which bowel movements are difficult or painful to pass and don’t happen very often.
  • Constipation is a common problem for people with cancer.
  • Assessment of constipation includes a health history, physical exam, and other tests.
  • It is important to prevent and treat constipation to avoid serious problems.

Constipation is a condition in which bowel movements are difficult or painful to pass and don’t happen very often.

Constipation is caused by the slow movement of stool through the large intestine. As the stool slowly moves through the large intestine, it loses fluid and becomes harder.

A person with constipation may be unable to have a bowel movement, have to push harder to have a bowel movement, or have infrequent bowel movements.

There is no “normal” number of bowel movements for a person with cancer. Each person is different. However, if you have infrequent bowel movements, you may be constipated.

Constipation is a common problem for people with cancer.

Common causes of constipation include older age, changes in diet and fluid intake, and not getting enough exercise. In addition to these common causes of constipation, other causes in people with cancer include:

  • Medicines. Chemotherapy, opioids, antidepressants, antacids, and diuretics can cause constipation by affecting the nerves and muscles in the digestive tract, slowing down bowel movements.
  • Changes in your bathroom habits. You may have little or no privacy and need help to get to the bathroom.
  • Limited mobility. Long periods of inactivity due to cancer can cause constipation.
  • Bowel disorders. This includes disorders such as irritable bowel and diverticulitis.
  • Muscle and nerve disorders. A spinal cord injury or pressure on the spinal cord from a tumor can cause constipation.
  • Metabolic changes. Some cancers can affect your appetite and ability to absorb, store, and use nutrients.
  • Depression. Depression can lead to lower levels of activity and changes in bodily functions. Constipation can also be a side effect of medicines that treat depression.

Assessment of constipation includes a health history, physical exam, and other tests.

The following tests and procedures may be done to help diagnose constipation:

  • Health history: A discussion with your doctor about your bowel habits, including frequency, stool consistency, and whether you are experiencing symptoms such as pain, bloating, or nausea when you are constipated. The doctor will also ask about your diet, fluid intake, and medicines you are taking and whether there have been recent changes in any of these areas. For people who have colostomies, care of the colostomy will be discussed.
  • Physical exam: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. The doctor will check the abdomen to see if it is swollen, listen for bowel sounds, and feel for painful areas in the abdomen.

If the cause of the constipation isn’t clear from the health history and physical exam, your doctor may order more tests to find out if another problem is causing the constipation:

  • Digital rectal exam (DRE): An exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual. In women, the vagina may also be examined.
  • Fecal occult blood test: A test to check stool for blood that can only be seen with a microscope. Small samples of stool are placed on special cards and returned to the doctor or laboratory for testing.
    EnlargeGuaiac fecal occult blood test (FOBT) kit; shows card, applicator, and return envelope.
    A guaiac fecal occult blood test (FOBT) checks for occult (hidden) blood in the stool. Small samples of stool are placed on a special card and returned to a doctor or laboratory for testing.
  • Abdominal x-ray: An x-ray of the organs inside the abdomen. An x-ray is a type of high-energy radiation that can go through the body and onto film, making a picture of areas inside the body.
  • Sigmoidoscopy: A procedure to look inside the rectum and sigmoid (lower) colon for polyps, abnormal areas, or cancer. A sigmoidoscope is inserted through the rectum into the sigmoid colon. A sigmoidoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.
  • Colonoscopy: A procedure to look inside the rectum and colon for polyps, abnormal areas, or cancer. A colonoscope is inserted through the rectum into the colon. A colonoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeColonoscopy; drawing shows a colonoscope inserted through the anus and rectum and into the colon. An inset shows a patient lying on a table having a colonoscopy.
    Colonoscopy. A thin, lighted tube is inserted through the anus and rectum and into the colon to look for abnormal areas.

It is important to prevent and treat constipation to avoid serious problems.

The health care team will talk to you about ways to prevent and treat constipation. Constipation can be uncomfortable and cause distress. If left untreated, constipation may lead to fecal impaction. This is a serious condition in which stool will not pass out of the colon or rectum. It’s important to treat constipation to prevent fecal impaction.

Prevention and treatment of constipation are not the same for every person. Keep track of how often you have a bowel movement and do the following to prevent and treat constipation:

  • Drink more fluid each day unless you have a medical condition that restricts fluid intake.
  • Get regular exercise. People who cannot walk may do abdominal exercises in bed or move from the bed to a chair.
  • Increase the amount of fiber in the diet. It’s important to drink more fluids when eating more high-fiber foods, to avoid making constipation worse. People who have had a small or large intestinal obstruction or have had intestinal surgery (for example, a colostomy) should not eat a high-fiber diet.
  • Drink a warm or hot drink about one half-hour before the usual time for a bowel movement.
  • Find privacy and quiet when it is time for a bowel movement.
  • Use the toilet or a bedside commode instead of a bedpan.
  • People who take opioids may need to start taking laxatives right away to prevent constipation. Other drugs may be given to prevent constipation.

People at risk of bleeding or infection should talk with their doctor before using suppositories or enemas.

Fecal Impaction

Key Points

  • Fecal impaction is a severe form of constipation in which dry, hard stool cannot pass out of the colon or rectum.
  • Fecal impaction and constipation share similar symptoms, but fecal impaction may cause other severe symptoms, such as breathing problems, dizziness, or low blood pressure.
  • Assessment of constipation includes a health history, physical exam, and other tests.
  • Fecal impaction is usually treated with an enema.

Fecal impaction is a severe form of constipation in which dry, hard stool cannot pass out of the colon or rectum.

Fecal impaction is dry stool that cannot pass out of the body. Constipation that is not treated can lead to fecal impaction. For this reason, the causes of fecal impaction are the same as those of constipation. To learn more, see the section on causes of constipation.

Fecal impaction and constipation share similar symptoms, but fecal impaction may cause other severe symptoms, such as breathing problems, dizziness, or low blood pressure.

Symptoms of fecal impaction include:

  • being unable to have a bowel movement
  • having to push harder to have a bowel movement of small amounts of hard, dry stool
  • having fewer than the usual number of bowel movements
  • having a swollen abdomen
  • having pain in the back or abdomen
  • urinating more or less often than usual, or being unable to urinate
  • having breathing problems
  • having a rapid heartbeat or chest pain
  • dizziness or low blood pressure
  • having sudden, explosive diarrhea (as stool moves around the impaction)
  • leaking stool when coughing
  • nausea and vomiting
  • dehydration
  • being confused and losing a sense of time and place, with a rapid heartbeat, sweating, fever, and high or low blood pressure

It’s important to talk with your health care provider if you have these symptoms.

Assessment of constipation includes a health history, physical exam, and other tests.

The following tests and procedures may be done to help diagnose fecal impaction:

  • Health history: A discussion with your doctor about your bowel habits, including frequency, stool consistency, and whether you are experiencing symptoms such as pain, bloating, or nausea when you are constipated. The doctor will also ask about your diet, fluid intake, and medicines you are taking and whether there have been recent changes in any of these areas.
  • Physical exam: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. The doctor will check the abdomen to see if it is swollen, listen for bowel sounds, and feel for painful areas in the abdomen.
  • Abdominal x-rays: An x-ray of the organs inside the abdomen. An x-ray is a type of high energy radiation that can go through the body and onto film, making a picture of areas inside the body to check for fecal impaction.
  • Digital rectal exam (DRE): An exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for a fecal impaction, lumps, or anything else that seems unusual.
  • Sigmoidoscopy: A procedure to look inside the rectum and sigmoid (lower) colon for a fecal impaction, polyps, abnormal areas, or cancer. A sigmoidoscope is inserted through the rectum into the sigmoid colon. A sigmoidoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeSigmoidoscopy; drawing shows a sigmoidoscope inserted through the anus and rectum and into the sigmoid colon. An inset shows a patient lying on a table having a sigmoidoscopy.
    Sigmoidoscopy. A thin, lighted tube is inserted through the anus and rectum and into the lower part of the colon to look for abnormal areas.

Fecal impaction is usually treated with an enema.

The main treatment for impaction is to moisten and soften the stool so it can be removed or passed out of the body. This is usually done with an enema. Enemas are given only as prescribed by the doctor to reduce the risk of bleeding or infection for patients with low blood counts and because too many enemas can damage the intestine. Some people may need to have stool manually removed from the rectum after it is softened.

Bowel Obstruction

Key Points

  • A bowel obstruction is a blockage of the small or large intestine by something other than fecal impaction.
  • A bowel obstruction can cause pain.
  • Assessment of a bowel obstruction includes a physical exam and imaging tests.
  • Treatment for acute bowel obstruction may include surgery.
  • Treatment of a chronic, malignant bowel obstruction may include surgery to improve quality of life.

A bowel obstruction is a blockage of the small or large intestine by something other than fecal impaction.

A bowel obstruction (blockage) may be caused by a twist in an intestine, a hernia, inflammation, scar tissue from surgery, or cancer. The obstruction keeps the stool from moving through the small or large intestines. The intestine may be partly or completely blocked and can sometimes be blocked in two places.

A bowel obstruction may cause decreased blood flow to an area of the intestines. Blood flow needs to be corrected or the affected tissue may die.

Cancers in the stomach, colon, and ovary can spread to the abdomen and cause an obstruction. People with these cancers or those who have had surgery or radiation therapy to the abdomen have a higher risk of a bowel obstruction. Bowel obstructions are most common during the advanced stages of cancer.

A bowel obstruction can cause pain.

The following may be symptoms of a bowel obstruction:

  • abdominal pain or cramps
  • swelling in the abdomen
  • constipation
  • diarrhea
  • nausea or vomiting
  • problems passing gas
  • loss of appetite

It’s important to talk with your health care provider if you have these symptoms.

Assessment of a bowel obstruction includes a physical exam and imaging tests.

The following tests and procedures may be done to diagnose a bowel obstruction:

  • Physical exam: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
  • Electrolyte panel: A blood test that measures the levels of electrolytes, such as sodium, potassium, and chloride.
  • Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, red blood cells, and white blood cells.
  • CT scan (CAT scan): This procedure uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the abdomen, taken from different angles. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Abdominal x-ray: An x-ray of the organs inside the abdomen. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Barium enema: A series of x-rays of the lower gastrointestinal tract. A liquid that contains barium (a silver-white metallic compound) is put into the rectum. The barium coats the lower gastrointestinal tract and x-rays are taken. This procedure is also called a lower GI series. This test may show what part of the intestine is blocked.
    EnlargeBarium enema procedure; shows barium liquid being put into the rectum and flowing through the colon. Inset shows person on table having a barium enema.
    Barium enema procedure. The patient lies on an x-ray table. Barium liquid is put into the rectum and flows through the colon. X-rays are taken to look for abnormal areas.

Treatment for acute bowel obstruction may include surgery.

Acute bowel obstructions occur suddenly and can be treated. Treatment may include the following:

  • Fluid replacement therapy: A treatment to get the fluids in the body back to normal amounts. Intravenous (IV) fluids may be given and medicines may be prescribed.
  • Electrolyte correction: A treatment to get the right amounts of chemicals in the blood, such as sodium, potassium, and chloride. Fluids with electrolytes may be given by infusion.
  • Blood transfusion: A procedure in which a person is given an infusion of whole blood or parts of blood.
  • Bowel rest: Food and sometimes fluid are held to give the intestines time to heal.
  • Nasogastric or colorectal tube: A nasogastric tube is inserted through the nose and esophagus into the stomach. A colorectal tube is inserted through the rectum into the colon. This is done to decrease swelling, remove fluid and gas buildup, and relieve pressure.
  • Stents: A metal tube inserted into the intestine to open the area that is blocked to relieve symptoms caused by the blockage.
  • Surgery: Surgery to relieve the obstruction may be done if it causes serious symptoms that are not relieved by other treatments.

People with symptoms that keep getting worse will have follow-up exams to check for signs and symptoms of shock and to make sure the obstruction isn’t getting worse.

Treatment of a chronic, malignant bowel obstruction may include surgery to improve quality of life.

Chronic, malignant bowel obstructions may worsen over time. People with advanced cancer may have chronic bowel obstructions that cannot be removed with surgery. The intestine may be blocked or narrowed in more than one place or the tumor may be too large to remove completely. Treatments include the following:

  • Surgery: The obstruction is removed to relieve pain and improve the patient’s quality of life.
  • Stent: A metal tube inserted into the intestine to open the area that is blocked to relieve symptoms and improve the patient’s quality of life.
  • Gastrostomy tube: A tube inserted through the wall of the abdomen directly into the stomach. The gastrostomy tube can be attached to a drainage bag with a valve. When the valve is open the built-up fluid and air can leave the stomach to relieve symptoms caused by the obstruction. People may also be able to eat or drink by mouth because the food drains directly into the bag. This gives the person the experience of tasting the food and keeping the mouth moist. Solid food is avoided because it may block the tubing to the drainage bag. If the person has an obstruction that is not completely blocking the intestine, they may also use the gastrostomy tube to pour medications directly into the stomach.
  • Medicines: Injections or infusions of medicines for pain, nausea and vomiting, and/or to make the intestines empty. This may be prescribed for people who cannot have surgery or be helped with a stent or gastrostomy tube.

Diarrhea

Key Points

  • Diarrhea is frequent, loose, and watery bowel movements.
  • Cancer treatment is the most common cause of diarrhea in people with cancer.
  • Assessment of diarrhea includes a health history, physical exam, and lab tests.
  • Treatment of diarrhea depends on what is causing it.

Diarrhea is frequent, loose, and watery bowel movements.

Acute diarrhea is three or more loose or watery bowel movements in one day. Acute diarrhea may last more than 4 days but less than 2 weeks. Frequent, watery stools that last for more than 2 months is called chronic diarrhea. Diarrhea can occur at any time during cancer treatment. It can be physically and emotionally stressful for people with cancer.

Cancer treatment is the most common cause of diarrhea in people with cancer.

Causes of diarrhea in people with cancer include the following:

Assessment of diarrhea includes a health history, physical exam, and lab tests.

Diarrhea can cause life-threatening complications in people with cancer. It is important to find out the cause so treatment can begin as soon as possible.

The following tests and procedures may be done to diagnose diarrhea and help plan treatment:

  • Health history: A discussion with your doctor about your urine habits and bowel habits, including frequency, stool consistency, and whether you are experiencing symptoms such as dizziness, drowsiness, pain, nausea and vomiting, or fever. The doctor will also ask about your recent diet and fluid intake, recent travels, and medicines you are taking and how often.
  • Physical exam: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. The doctor will check the abdomen for painful areas and listen for bowel sounds.
  • Digital rectal exam (DRE): An exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual. The exam will check for signs of fecal impaction. Stool may be collected for laboratory tests.
  • Fecal occult blood test: A test to check stool for blood that can only be seen with a microscope. Small samples of stool are placed on special cards and returned to the doctor or laboratory for testing.
  • Stool tests: Laboratory tests to check the water and sodium levels in stool, and to find substances that may be causing diarrhea. Stool is also checked for bacterial, fungal, or viral infections.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
  • Electrolyte panel: A blood test that measures the levels of electrolytes, such as sodium, potassium, and chloride.
  • Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, red blood cells, and white blood cells.
  • Abdominal x-ray: An x-ray of the organs inside the abdomen. An x-ray is a type of high-energy radiation that can go through the body and onto film, making a picture of areas inside the body. Abdominal x-rays may also be done to look for a bowel obstruction or other problems.

Treatment of diarrhea depends on what is causing it.

Treatment depends on the cause of the diarrhea. The doctor may make changes to your medicines, diet, and/or fluids. Treatment of diarrhea may include the following:

  • A change in the use of laxatives may be needed.
  • Medicine to treat diarrhea may be prescribed to slow down the intestines, decrease fluid secreted by the intestines, and help nutrients be absorbed.
  • Diarrhea caused by cancer treatment may be treated by changes in diet. Eat small frequent meals and avoid the following foods:
    • milk and dairy products
    • spicy foods
    • alcohol
    • foods and drinks that have caffeine
    • certain fruit juices
    • foods and drinks that cause gas
    • foods high in fiber or fat
  • Drink more clear liquids to help stay hydrated. These include water, sports drinks, broth, weak decaffeinated tea, caffeine-free soft drinks, clear juices, and gelatin. For severe diarrhea, the person may need intravenous (IV) fluids or other forms of IV nutrition.
  • Diarrhea caused by graft-versus-host-disease (GVHD) is often treated with a special diet. Some people may need long-term treatment and diet management.
  • Probiotics may be suggested. Probiotics are live microorganisms used as a dietary supplement to help with digestion and normal bowel function. Research on the use of Lactobacillus acidophilus and Bifidobacterium has reported benefits in treating diarrhea.
  • People who have diarrhea with other symptoms may need fluids and medicine given by IV.

Radiation Enteritis

Key Points

  • Radiation enteritis is inflammation of the intestine caused by radiation therapy.
  • The total dose of radiation and other factors affect the risk of radiation enteritis.
  • Acute and chronic radiation enteritis have similar symptoms.
  • Assessment of radiation enteritis includes a physical exam and health history.
  • Treatment of acute radiation enteritis includes treating the symptoms.
  • Treatment of chronic radiation enteritis may include the same treatments for acute radiation enteritis.

Radiation enteritis is inflammation of the intestine caused by radiation therapy.

The small and large intestine are sensitive to radiation. Radiation therapy given to kill cancer cells in the abdomen and pelvis affects normal cells in the lining of the intestines. Radiation therapy stops the growth of cancer cells and other fast-growing cells. Since normal cells in the lining of the intestines grow quickly, radiation treatment to that area can stop those cells from growing. This makes it hard for tissue to repair itself. As cells die and are not replaced, gastrointestinal problems occur over the next few days and weeks.

Radiation enteritis is a condition in which the lining of the intestine becomes swollen and inflamed during or after radiation therapy to the abdomen, pelvis, or rectum. The larger the dose of radiation, the more damage may be done to normal tissue.

Radiation enteritis may be acute or chronic:

  • Acute radiation enteritis occurs during radiation therapy or within three months after finishing radiation therapy.
  • Chronic radiation enteritis may appear months after radiation therapy ends.

The total dose of radiation and other factors affect the risk of radiation enteritis.

The amount of time the enteritis lasts and how severe it is depend on the following:

  • the type and total dose of radiation received
  • the amount of normal intestine treated
  • the tumor size and how much it has spread
  • if chemotherapy was given at the same time as the radiation therapy
  • if the person has had surgery to the abdomen or pelvis
  • if the person has high blood pressure, diabetes, a smoking history, or poor nutrition

About 10% to 20% of people treated with radiation to the abdomen will have chronic problems.

Acute and chronic radiation enteritis have similar symptoms.

People with acute radiation enteritis may have the following symptoms:

Symptoms of acute enteritis usually go away 2 to 3 weeks after treatment ends.

Symptoms of chronic radiation enteritis usually appear 6 to 18 months after radiation therapy ends. It can be hard to diagnose. The doctor will first check to see if the symptoms are being caused by a recurrent tumor in the intestine. The doctor will also need to know the person’s full history of radiation treatments.

People with chronic radiation enteritis may have the following signs and symptoms:

  • abdominal pain
  • bloody diarrhea
  • greasy and fatty stools
  • weight loss
  • nausea
  • vomiting

It’s important to talk with your health care provider if you have these symptoms.

Assessment of radiation enteritis includes a physical exam and health history.

A doctor will do a physical exam and ask questions about the following:

  • usual pattern of bowel movements
  • pattern of diarrhea:
    • when it started
    • how long it has lasted
    • how often it occurs
    • amount and type of stools
    • other symptoms with the diarrhea (such as gas, cramping, bloating, urgency, bleeding, and rectal soreness)
  • nutrition health:
    • height and weight
    • usual eating habits
    • changes in eating habits
    • amount of fiber in the diet
    • signs of dehydration (such as poor skin tone, increased weakness, or feeling very tired)
  • stress levels and ability to cope
  • changes in lifestyle caused by the enteritis

Treatment of acute radiation enteritis includes treating the symptoms.

The symptoms of radiation enteritis usually get better with treatment, but if symptoms get worse, then cancer treatment may have to be stopped for a while.

Treatment of acute radiation enteritis or the symptoms may include:

  • anti-inflammatory medicines that improve the flow of blood through the body
  • antibiotics
  • steroids
  • medicines to stop diarrhea and to lower cholesterol in the blood
  • vitamin E
  • probiotic
  • diet changes
    • Intestines damaged by radiation therapy may not make enough of certain enzymes needed for digestion, especially lactase. Lactase is needed to digest lactose, which is found in milk and milk products. A lactose-free, low-fat, and low-fiber diet may help control symptoms of acute enteritis. Foods to avoid:
      • milk and some milk products
      • whole-bran bread and cereal
      • nuts, seeds, and coconut
      • fried, greasy, or fatty foods
      • fresh and dried fruit and some fruit juices (such as prune juice)
      • raw vegetables
      • rich pastries
      • popcorn, potato chips, and pretzels
      • strong spices and herbs
      • chocolate, coffee, tea, and soft drinks with caffeine
      • alcohol and tobacco
    • Foods to choose:
      • fish, poultry, and meat that are broiled or roasted
      • bananas
      • applesauce and peeled apples
      • apple and grape juices
      • white bread and toast
      • pasta
      • baked, boiled, or mashed potatoes
      • cooked vegetables that are mild, such as asparagus tips, green and waxed beans, carrots, spinach, and squash
      • mild processed cheese, which may not cause problems because the lactose is removed when it is made
      • buttermilk, yogurt, and lactose-free milkshake supplements, such as Ensure
      • eggs
      • smooth peanut butter
    • Helpful hints:
      • Eat food at room temperature.
      • Drink about 12 eight-ounce glasses of fluid a day.
      • Let sodas lose their fizz before drinking them.
      • Add nutmeg to food. This helps slow down movement of digested food in the intestines.
      • Start a low-fiber diet on the first day of radiation therapy.

Treatment of chronic radiation enteritis may include the same treatments for acute radiation enteritis.

Treatment of chronic radiation enteritis may include the following:

  • same treatments as for acute radiation enteritis symptoms
  • surgery may be needed to control symptoms in some patients. Two types of surgery may be used:
    • Intestinal bypass: A procedure in which the doctor creates a new pathway for the flow of intestinal contents around the damaged tissue.
    • Total intestinal resection: Surgery to completely remove the intestines.

    Doctors look at the person’s general health and the amount of damaged tissue before deciding if surgery will be needed. Healing after surgery is often slow and long-term tubefeeding may be needed. Even after surgery, many people still have symptoms.

Current Clinical Trials

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Gastrointestinal Complications

For more information from the National Cancer Institute about constipation or diarrhea, see the following:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the causes and treatment of gastrointestinal complications, including constipation, impaction, bowel obstruction, diarrhea, and radiation enteritis. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Supportive and Palliative Care Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Gastrointestinal Complications. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /side-effects/constipation/GI-complications-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389438]

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Sleep Problems in People with Cancer


Sleep Problems in People with Cancer

Man with cancer who is getting good night’s sleep in a comfortable bed.

People going through treatment for cancer may have changes in their sleep patterns or difficulty sleeping. Tell your nurse about any difficulties you are having, so you can get the help you need to sleep better at night. 

Credit: iStock

What sleep problems are common in people being treated for cancer?

Sleep problems such as being unable to fall asleep and/or stay asleep, also called insomnia, are common among people being treated for cancer.

What causes sleep problems?

Sleep problems may be caused by the side effects of treatment, medicines you are taking, long hospital stays, stress, and other factors. Studies show that as many as half of all people have sleep-related problems during treatment for cancer.

How are sleep problems assessed?

Your doctor, or a sleep specialist, can do an assessment, which may include a polysomnogram (recordings taken during sleep that show brain waves, breathing rate, and other activities such as heart rate) to correctly diagnose and treat sleep problems. Assessments may be repeated from time to time, since sleeping problems may change over time. Learn more about when a sleep study may be useful, what to expect, and what your doctor may recommend after a sleep study. 

Why is a good night’s sleep important?

Sleeping well is important for your physical and mental health. A good night’s sleep may help you to think more clearly, lower your blood pressure, help your appetite, and strengthen your immune system. Sleep problems that go on for a long time may increase the risk of anxiety or depression.

Ways to manage sleep problems 

Talk with your health care team if you have difficulty sleeping, so you can get the help you need. There are steps that you and your health care team can take to help you sleep well again.

  • Tell your doctor about problems that interfere with sleep. Getting treatment to lower problems such as pain or other side effects such as urinary and bladder problems, or diarrhea, may help you sleep better.
  • Cognitive behavioral therapy (CBT) and relaxation therapy may help. Practicing these therapies can help you to relax. For example, a CBT therapist can help you learn to change negative thoughts and beliefs about sleep into positive ones. Strategies such as muscle relaxation, guided imagery, and self-hypnosis may also help you.
  • Set good bedtime habits. Go to bed only when sleepy, in a quiet and dark room, and in a comfortable bed. If you do not fall asleep, get out of bed and return to bed when you are sleepy. Stop watching television or using other electrical devices a couple of hours before going to bed. Don’t drink or eat a lot before bedtime. While it’s important to keep active during the day with regular exercise, exercising a few hours before bedtime may make sleep more difficult.
  • Sleep medicine may be prescribed. Your doctor may prescribe sleep medicine, for a short period if other strategies don’t work. The sleep medicine prescribed will depend on your specific problem (such as trouble falling asleep or trouble staying asleep) as well as other medicines you are taking.

Talking with your health care team about sleep problems

Prepare for your visit by making a list of questions to ask. Consider adding these questions to your list:

  • Why am I having trouble sleeping?
  • What problems should I call you about?
  • What steps can I take to sleep better?
  • Would you recommend a sleep therapist who could help with the problems I am having?
  • Would sleep medicine be advised for me?

Skin and Nail Changes during Cancer Treatment


Skin and Nail Changes during Cancer Treatment

Person with cancer applying lotion to prevent dry and itchy skin.

When cancer treatments cause skin and nail problems, there are creams and lotions that can help your skin to feel better.

Credit: iStock

Cancer treatments may cause skin and nail changes. Talk with your health care team to learn what side effects your treatment may cause. While skin problems caused by radiation therapy and chemotherapy are often mild, they may be more severe if you are receiving a stem cell transplant, targeted therapy, or immunotherapy. Let your health care team know if you notice any skin changes so they can be treated promptly.

  • Sometimes radiation therapy can cause the skin on the part of your body receiving radiation to become dry and peel, itch (called pruritus), and turn red or darker. Your skin may look sunburned or become swollen or puffy. You may develop sores that become painful, wet, and infected. This is called a moist reaction.
  • Some types of chemotherapy can cause your skin to become dry, itchy, red or darker, or peel. You may develop a minor rash or sunburn easily; this is called photosensitivity. Some people also have skin pigmentation changes. Your nails may be dark and cracked, and your cuticles may hurt. If you received radiation therapy in the past, the area of skin where you received radiation may become red, blister, peel, or hurt. This is called radiation recall. Signs of an allergic response to chemotherapy may include a sudden or severe rash or hives or a burning sensation.
  • Stem cell transplants can cause graft-versus-host disease (GVHD), which may cause skin problems such as a rash, blisters, or thickening of the skin.
  • Some types of immunotherapy can cause a severe and sometimes extensive rash. Your skin may be dry or blister.
  • Some types of targeted therapy may cause dry skin, a rash, and nail problems. If you develop a rash, it is important to talk with your doctor before stopping targeted therapy.

Ask Your Health Care Team about Skin and Nail Changes

  • What skin and nail changes might I have, based on the cancer treatment I am receiving?
  • Which symptoms can be managed at home? Which symptoms need urgent medical care?

If you have a severe, extensive, blistering, or painful rash and are receiving immunotherapy, call your doctor to get their advice. It’s especially important to call about rashes that involve the eyes or a mucous membrane, such as your mouth, caused by immunotherapy.

Make note of all problems you should call your health care team about.

Skin changes:

Nail changes:

  • cracked nails
  • cuticles that are swollen and/or painful
  • nail infections (acute paronychia)
  • yellow nails

Ways to prevent or manage mild skin and nail changes during cancer treatment

Talk with your health care team to learn if you should manage these problems at home. Depending upon the treatment you are receiving, your health care team may advise you to take these steps:

  • Use only recommended skin products. Use mild soaps that are gentle on your skin. Ask your nurse to recommend specific skin products. If you are receiving radiation therapy, ask about skin products, such as powder or antiperspirant, that you should avoid using before treatment.
  • Prevent infection. Radiation therapy can cause skin in the treatment area to peel, become painful, and wet. Most often this happens in areas where the skin folds, such as around your ears, breast, or bottom. Try to keep the area clean and dry so it does not become infected. Your nurse will talk with you about how to clean the area and may prescribe special dressings that you can apply to the area and/or antibiotics.
  • Moisturize your skin. Use recommended creams or lotions to prevent your skin from becoming dry and itchy. Irritated skin can become infected. Ask about special creams or ointments for severely dry, itchy, or painful skin.
  • Protect your skin. Use sunscreen and sun-protective lip balm. Wear a loose-fitting long-sleeved shirt, pants, and a hat with a wide brim when outdoors to prevent sunburn. If you are receiving radiation therapy, don’t use heating pads, ice packs, or bandages on the treatment area. You may want to shave less often and use an electric razor or stop shaving if your skin is tender and sore.
  • Prevent or treat dry, itchy skin. Avoid products that list alcohol or fragrance as an ingredient, since they can dry or irritate your skin. Your nurse may suggest you add colloidal oatmeal to your baths, as it can reduce itching. Take short showers or baths in lukewarm, not hot, water. Put on skin cream or ointment that is recommended by your nurse after drying off from a shower but while your skin is still a little damp. Apply a cool washcloth or ice to dry, itchy skin.
  • Prevent or treat minor nail problems. Keep your nails clean and cut short to avoid accidentally tearing them. Protect your hands and nails by wearing gloves when you wash the dishes, or clean the house, for example. Avoid getting manicures and pedicures. Don’t wear tight-fitting shoes. Ask your nurse to recommend products that can be used to treat nail problems.
  • Learn about treatments for irritating or painful skin rashes. Sometimes skin problems need medical treatment. Your rash may be treated with a medicated cream (topical corticosteroids) or with medicine that you take as a pill (oral corticosteroids or antibiotics).

Talking with your health care team about skin and nail changes

Prepare for your visit by making a list of questions to ask. Consider adding these questions to your list:

  • What skin-and nail related side effects are common for the type of treatment I’m receiving?
  • Are there steps I can take to prevent any of these problems?
  • What problems should I call you about? Are there any problems that need urgent medical care?
  • When might these problems start? How long might they last?
  • What brands of soap and lotion would you advise me to use on my skin? On my nails?
  • Are there skin and nail products I should avoid?
  • Should I see a dermatologist so I can learn more about how to prevent or manage skin problems?

Listen to tips on how to manage mild skin changes caused by cancer treatments such as radiation therapy.
(Type: MP3 | Time: 2:20 | Size: 2.2MB)

Urinary and Bladder Problems


Urinary and Bladder Problems

Older man who is drinking a full glass of water.

For urinary and bladder problems caused by cancer treatments, drink plenty of water. Ask your doctor what symptoms to call about—such as fever or pain, for example.

Credit: iStock

Some cancer treatments, such as those listed below, may cause urinary and bladder problems:

Symptoms of a urinary problem

Talk with your doctor or nurse to learn what symptoms you may experience and ask which ones to call about. Some urinary or bladder changes may be normal, such as changes to the color or smell of your urine caused by some types of chemotherapy. Your health care team will determine what is causing your symptoms and will advise on steps to take to feel better.

Irritation of the bladder lining (radiation cystitis):

  • pain or a burning feeling when you urinate
  • blood in your urine (hematuria)
  • trouble starting to urinate
  • trouble emptying your bladder completely (urinary retention)
  • feeling that you need to urinate urgently or frequently
  • leaking a little urine when you sneeze or cough
  • bladder spasms, cramps, or discomfort in the pelvic area

Urinary tract infection (UTI):

  • pain or a burning feeling when you urinate
  • urine that is cloudy or red
  • a fever of 100.5 °F (38 °C) or higher, chills, and fatigue
  • pain in your back or abdomen
  • difficulty urinating or not being able to urinate

In people being treated for cancer, a UTI can turn into a serious condition that needs immediate medical care. Antibiotics will be prescribed if you have a bacterial infection.

Symptoms that may occur after surgery:

Ways to prevent or manage

Here are some steps you may be advised to take to feel better and to prevent problems:

  • Drink plenty of liquids. Most people need to drink at least 8 cups of fluid each day, so that urine is light yellow or clear. You’ll want to stay away from things that can make bladder problems worse. These include caffeine, drinks with alcohol, spicy foods, and tobacco products.
  • Prevent urinary tract infections. Your doctor or nurse will talk with you about ways to lower your chances of getting a urinary tract infection. These may include going to the bathroom often, wearing cotton underwear and loose fitting pants, learning about safe and sanitary practices for catheterization, taking showers instead of baths, and checking with your nurse before using products such as creams or lotions near your genital area.

Talking with your health care team

Prepare for your visit by making a list of questions to ask. Consider adding these questions to your list:

  • What symptoms or problems should I call you about?
  • What steps can I take to feel better?
  • How much should I drink each day? What liquids are best for me?
  • Are there certain drinks or foods that I should avoid?

 

Listen to tips on how to manage changes when you urinate caused by cancer treatments such as radiation therapy.
(Type: MP3 | Time: 3:04 | Size: 2.9MB)

Pain and Cancer


Pain and Cancer

Doctor explaining when and how often to take medicine for pain, to a man with cancer.

Taking pain medicine is an important part of your cancer treatment plan.

Credit: iStock

Having cancer doesn’t mean that you’ll have pain. But if you do, pain can usually be controlled with pain medicine and non-drug approaches. Pain may be caused by cancer or cancer treatment. The information on this page will help you talk with your doctor to develop a pain management strategy to relieve your pain.

Key facts about pain for people with cancer

  • Controlling pain is an important part of your cancer treatment plan. You may have pain that feels more intense at times than others. Therefore, sometimes you may need stronger medicines or different approaches to control the pain.
  • Your doctor will develop a pain control plan that is unique to you, based on your symptoms and what is causing the pain.
  • Tell your health care team how the plan to control pain is working. Trying to “deal with” the pain can make it harder to control in the future.
  • Effectively treating pain can make a big difference in your everyday life, as well as improve your mood, help you sleep better, and give you energy.

Common types of pain in people with cancer

  • Acute pain, which may feel sharp and come on quickly. It often lasts for only a short time.
  • Breakthrough pain, which may come on suddenly, is pain that may occur while you are taking medicine to manage chronic pain. It usually lasts for a short time and may be intense. Breakthrough pain may happen even when you’re taking the correct amount of pain medicine, if the current medicine is wearing off, for example.
  • Chronic pain, also called persistent pain, is pain that usually lasts more than three months. It may be mild or severe. Chronic pain may come and go or be constant. Chronic pain levels may also stay the same, or get worse, over time.

There are different causes of pain in people being treated for cancer. Sometimes cancer is the cause of your pain. This may happen if a tumor presses on nerves or other parts of your body. Some cancer treatments or tests cause pain, such as surgery or bone marrow aspiration. Another cause of pain may be the side effects of cancer treatment, such as mouth sores, peripheral neuropathy, or skin reactions.

Specialists who treat people with pain

Some hospitals have pain specialists. These specialists often work together as a team to treat pain. Your pain control team may be led by your doctor or a palliative care specialist. Other specialists on the team may include experts such as a nurse, an acupuncturist, a pharmacist, a surgeon, a psychiatrist or a psychologist.

Developing a pain control plan 

Based on your description of the pain, your symptoms, a physical exam, and sometimes imaging tests, your doctor will develop a plan to control your pain. This plan usually includes pain control medicine and may include other practices such as those listed in the integrative medicine section below.

Describing your pain: When you talk with your doctor or nurse, be as specific as you can about the pain. Your health care team may ask you questions like these to better understand and treat your pain: 

  • Where do you feel pain? 
  • What does the pain feel like (is it sharp, burning, shooting, or throbbing)? Here are words you can use to help describe pain.
  • Does the pain come and go, or is it constant?
  • When does the pain start? How long does the pain last?
  • How bad is the pain, on a scale of 1 to 10, where “10” is the most pain and “1” the least?
  • What helps to lower the pain or make it go away?
  • What makes the pain get worse?
  • Does the pain interfere with eating, sleeping, exercise, or other daily activities? 
  • How does pain affect your mood and mental health?

Ask your nurse how to track pain-related information. Some people write down their levels of pain and the medicine they took for it, in a notebook. Others may get a chart from their nurse or use a pain app on their phone.    

Getting a pain control plan that works for you: Once a pain control plan has been developed, your health care team will talk with you about whether your pain is going down. They may ask you questions:

  • Is your pain medicine helping to lower the pain?
  • How much medicine do you take?
  • When and how often do you take it?
  • Is the pain medicine causing side effects that are bothering you?
  • Would you like to try other practices that may help with your pain? For example, acupuncture, mindfulness, hypnosis, or guided imagery.

Based on your answers to these questions, your doctor may change the type or amount of pain medicine and make other suggestions.

When to call your doctor: Contact your doctor or nurse if you feel new pain, if your pain isn’t decreasing or going away with pain medicine, or if you have side effects from the pain medicine. Pain is not something that you have to “put up with.” Ask your doctor about any other times you should call.

Taking your pain control medicine

Different types of pain medicine (also called painkillers, pain relievers, and analgesics) are used to control pain. Your doctor will explain what medicine is recommended for you, when to take it, and exactly how much to take (dose) at one time. It’s also important to learn about side effects and how to manage them.

Types of pain medicine

These different types of medicine may be used to control pain:

Learn more about these and other drugs in the NCI Drug Dictionary. 

How much and when to take pain control medicine

Cancer Pain Control: Support for People With Cancer

Learn what you can do to help manage the physical and emotional effects of cancer-related pain.

Take the prescribed amount of medicine, at the scheduled time. If you aren’t sure exactly when to take your pain medicine, ask your doctor.

  • Don’t wait until your pain gets bad before taking pain medicine. If you wait to take your medicine, the pain may take longer to go away, or you may need to take more medicine. The best way to control pain is to stop it from starting or keep it from getting worse.  
  • Tell your doctor if the medicine is not working. The type of pain medicine or the amount you are taking may need to be changed.
  • Never stop taking your pain medicine without first talking to your doctor. Taking less pain medicine than your doctor has prescribed or stopping the medication abruptly could cause a condition called withdrawal. Symptoms of withdrawal may include anxiety, sweating, nausea, and vomiting.
  • Sometimes your body gets used to a medicine and it no longer works as it first did. This is called drug tolerance. Either more medicine or a different type of medicine may be prescribed.

Side effects of pain control medicines

It’s important to ask about side effects that pain medicine may cause so you know what to expect and how to manage them. Common side effects of pain medicine include constipation, drowsiness, nausea, or vomiting. Some of these may go away as your body gets used to the pain medicine. Talk with your doctor to learn about any reactions you should seek emergency medical care for or call about.

What to know about drug tolerance, physical dependence, and addiction

People with cancer often need to take strong pain medicine, such as opioids. Ask your health care team about drug tolerance, physical dependence, and addiction, especially if you were prescribed opioids to control pain.

Drug tolerance is a condition that happens when your body gets used to medicine. Some people with cancer pain stop getting pain relief from pain medicine over time. If drug tolerance happens, your doctor may increase the dose or prescribe a different pain medicine.

Physical dependence is a condition in which a person takes a drug over time and has unpleasant physical symptoms if the drug is suddenly stopped, or the dose is significantly reduced. It happens when the body gets used to a certain level of the medicine. Physical dependence can happen with the chronic use of a drug, even when taken as instructed.

Addiction involves compulsive drug seeking behavior and the inability to stop taking the drug, despite harmful consequences—such as not meeting important family, work, or social obligations. Know that addiction can happen to anyone, regardless of age, race, or income levels.

It’s common for people with cancer to worry about becoming addicted to pain medicines. Know that needing a higher dose of pain medicine or having symptoms when the dose is decreased or stopped is not the same as addiction. Your doctor will carefully prescribe your pain medicine and monitor you, so that your pain is safely treated. Each person’s pain control plan is tailored to them. Most people with cancer who take strong pain medicine, such as opioids, use them safely and effectively.

Complementary and integrative medicine practices to manage pain

In addition to prescribing medicine to manage pain, your health care team may suggest other practices. These non-drug practices are often called complementary medicine, integrative medicine, and whole person health. Some examples of natural pain relief include:

  • Acupuncture is the technique of inserting very thin needles about the thickness of a hair into specific points on your body. It can help to relieve discomfort and pain. Learn about acupuncture.
  • Biofeedback is a technique that helps you learn how to control functions such as heartbeat, blood pressure, and muscle tension to reduce pain. Learn about biofeedback-assisted relaxation.
  • Distraction is a technique that can help you take your attention away from the pain by focusing on something else, such as listening to music, walking outside, or watching a movie.
  • Guided imagery, also called visualization, is a technique in which you focus on positive scenes, pictures, or experiences to lower pain. Learn about guided imagery.
  • Hypnosis is a trance-like state of deep relaxation that can be used to relieve pain. Learn about hypnosis.
  • Meditation can help to relax your mind and body, which can improve your overall sense of well-being and lower pain. Learn about meditation and mindfulness.

These and other integrative medicine practices are available in communities and hospitals. There are also online programs. Ask your health care team to suggest the best options for you.  

Questions to ask doctors about pain 

  • What symptoms should I call you about?
  • What symptoms should I go to the emergency room for?
  • Which medicine(s) do you recommend for me?
  • What side effects may I have from the pain medicine?
  • If the pain doesn’t go away, can I take more pain medicine or take it more frequently?
  • If so, how much and how often can I take the pain medicine?
  • Is there a pain specialist that you could refer me to for more information?
  • Are there approaches other than or in addition to pain medication that may help my pain? 

NCI’s Cancer Pain PDQ summary has in-depth information on managing and treating cancer-associated pain. View the patient or health professional version.

Sexual Health Issues in Women with Cancer


Sexual Health Issues in Women with Cancer

Man and woman holding hands as they walk in the sunshine.

Talk with your doctor to learn what to expect and how to manage changes that may affect your sexual life.

Credit: iStock

Women being treated for cancer may experience changes that affect their sexual life during, and sometimes after, treatment. While you may not have the energy or interest in sexual activity that you did before treatment, feeling close to and being intimate with your spouse or partner is probably still important.

Your doctor or nurse may talk with you about how cancer treatment might affect your sexual life, or you may need to be proactive and ask questions such as: What sexual changes or problems are common among women receiving this type of treatment? What methods of birth control or contraception are recommended during treatment?

Other questions to consider asking are listed at the end of this page. For more information about how treatment may affect your fertility, see Fertility Issues in Girls and Women.

Whether or not your sexual health will be affected by treatment depends on factors such as:

  • the type of cancer
  • the type of treatment(s)
  • the amount (dose) of treatment
  • the length (duration) of treatment
  • your age at time of treatment
  • the amount of time that has passed since treatment
  • other personal health factors

Cancer treatments may cause sexual problems in women

Some problems that affect a woman’s sexual health during treatment are temporary and improve once treatment has ended. Other side effects may be long term or may start after treatment. Your doctor will talk with you about side effects you may have based on your treatment(s):

Ways to manage sexual health issues

People on your health care team have helped others to cope during this difficult time and can offer valuable suggestions. You may also want to talk with a sexual health expert to get answers to any questions or concerns.

Most women can be sexually active during treatment, but you’ll want to confirm this with your doctor. For example, there may be times during treatment when you are at increased risk of infection or bleeding and may be advised to abstain from sexual intercourse.

Your health care team can help you:

  • Learn about medicine and exercises to make sex more comfortable, including:
    • vaginal gels or creams to stop a dry, itchy, or burning feeling
    • vaginal lubricants or moisturizers
    • vaginal estrogen cream that may be appropriate for some types of cancer
    • a dilator to help prevent or reverse scarring, if radiation therapy or graft-versus-host disease has affected your vagina
    • exercises for pelvic muscles to lower pain, improve bladder retention, improve bowel function, and increase the flow of blood to the area, which can improve your sexual health
  • Manage related side effects: Talk with your doctor or nurse about problems such as pain, fatigue, hair loss, loss of interest in activities, sadness, or trouble sleeping, that may affect your sex life. Speaking up about side effects can help you get the treatment and support you need to feel better.
  • Learn about condoms and/or contraceptives: Condoms may be advised to prevent your partner’s exposure to some types of chemotherapy that may remain in vaginal secretions. If you are of childbearing age, contraceptives may be advised to prevent pregnancy while you are receiving treatment and for a period of time following treatment. For more information, see Fertility Issues in Girls and Women.
  • Get support and counseling: During this time, you can gain strength and support by sharing your concerns with people you are close to. You may also benefit from participating in a professionally moderated or led support group. Your nurse or social worker can recommend support groups and counselors in your area.

Learn more about organizations that provide support by visiting our database of national organizations that offer cancer-related support services and choosing from a list of services.

Talking with your health care team about sexual health issues

As you think about the changes that treatment has brought into your life, make a list of questions to discuss with your doctor, nurse, or social worker. Consider adding these to your list:

  • What sexual problems are common among women receiving this treatment?
  • What sexual problems might I have during treatment?
  • When might these changes occur?
  • How long might these problems last? Will any of these problems be permanent?
  • How can these problems be prevented, treated, or managed?
  • What specialist(s) would you suggest that I talk with to learn more?
  • Are there support groups in this area that you recommend?
  • What method(s) of birth control are advised?
  • What precautions do I need to take during treatment? For example, should my partner use a condom? Are there times when I should avoid sexual activity?

Listen to tips on how to manage changes in sexuality and fertility caused by cancer treatments such as radiation therapy.
(Type: MP3 | Time: 3:55 | Size: 3.7MB)

Sexual Health Issues in Men with Cancer


Sexual Health Issues in Men with Cancer

Man with cancer who is resting and being gently held by his wife.

Talk with your doctor to learn what to expect and how to manage changes that may affect your sexual life.

Credit: iStock

Men being treated for cancer may experience changes that affect their sexual life during, and sometimes after, treatment. While you may not have the energy or interest in sexual activity that you did before treatment, being intimate with and feeling close to your spouse or partner is probably still important.

Your doctor or nurse may talk with you about how cancer treatment might affect your sexual life or you may need to be proactive and ask questions such as: What sexual changes or problems are common among men receiving this type of treatment? What methods of birth control or protection are recommended during treatment?

Other questions to consider asking are listed at the end of this page. For more information about how treatment may affect your fertility, see Fertility Issues in Boys and Men. 

Whether or not you’ll have problems that affect your sexual health depends on factors such as:

  • the type of cancer
  • the type of treatment(s)
  • the amount (dose) of treatment
  • the length (duration) of treatment
  • your age at time of treatment
  • the amount of time that has passed since treatment
  • other personal health factors

Cancer treatments may cause sexual problems in men

Many problems that affect a man’s sexual activity during treatment are temporary and improve once treatment has ended. Other side effects may be long term or may start after treatment.

Your doctor will talk with you about side effects you may have based on your treatment(s):

Health problems, such as heart disease, high blood pressure, diabetes, and smoking, can also contribute to changes in your sexual health.

Ways to manage sexual health issues

People on your health care team have helped others cope during this difficult time and can offer valuable suggestions. You may also want to talk with a sexual health expert to get answers to any questions or concerns.

Most men can be sexually active during treatment, but you’ll want to confirm this with your doctor. For example, there may be times during treatment when you are at increased risk of infection or bleeding and may be advised to abstain from sexual activity. Depending on the type of treatment you are receiving, condom use may be advised.

Your health care team can help you:

  • Learn about treatments: Based on symptoms you are having, your oncologist or a urologist will advise you on treatment options. For example, there are medicines and devices that may be prescribed once a sexual health problem has been diagnosed. Medicines can be given to increase blood flow to the penis. There are also surgical procedures in which a firm rod or inflatable device (penile implant) is placed in the penis, making it possible to get and keep an erection.
  • Learn about condoms and/or contraceptives: Condoms may be advised to prevent your partner’s exposure to chemotherapy drugs that may remain in semen. Based on your partner’s age, contraception may be advised to prevent pregnancy. For more information, see Fertility Issues in Boys and Men.
  • Manage related side effects: Talk with your doctor or nurse about problems such as pain, fatigue, hair loss, loss of interest in activities, sadness, or trouble sleeping, that may affect your sex life. Speaking up about side effects can help you get the treatment and support you need to feel better.
  • Get support and counseling: During this time, it will help to share your feelings and concerns with people you are close to. You may also benefit from participating in a professionally moderated or led support group. Your nurse or social worker can recommend support groups and counselors in your area.

Learn more about organizations that provide support by visiting our database of national organizations that offer cancer-related support services and choosing from a list of services.

Talking with your health care team about sexual health issues

As you think about the changes that treatment has brought into your life, make a list of questions to ask your doctor, nurse, or social worker. Consider adding these to your list:

  • What sexual problems are common among men receiving this treatment?
  • What sexual problems might I have during treatment?
  • When might these changes occur?
  • How long might these problems last? Will any of these problems be permanent?
  • How can these problems be prevented, treated, or managed?
  • What precautions do I need to take during treatment? For example, do I need to use a condom to protect my partner?
  • Should my partners and I use contraception to avoid a pregnancy? What types of contraception (birth control) do you recommend?
  • Is there a support group that you recommend?
  • What specialist(s) would you suggest that that I talk with to learn more?

Listen to tips on how to manage changes in sexuality and fertility caused by cancer treatments such as radiation therapy.
(Type: MP3 | Time: 3:19 | Size: 3.1MB)